中药对血管内皮生长因子的治疗潜力

Therapeutic potential of traditional Chinese medicine for vascular endothelial growth factor 中药对血管内皮生长因子的治疗潜力 1 first-author https://orcid.org/0000-0002-3621-7485 1 2 corresp Huayi LIU, 15900369830@163.com Huayi LIU, 15900369830@163.com 15900369830@163.com https://orcid.org/0000-0002-7571-7335 1 2 1 1 1 Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301608, China Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin 300120, China Vascular endothelial growth factor (VEGF) is the main regulator of physiological angiogenesis during embryonic development, bone growth, and reproductive function, and it also participates in a series of pathological changes. Traditional Chinese medicine (TCM), with a history of more than 2000 years, has been widely used in clinical practice, while the exploration of its mechanisms has only begun. This review summarizes the research of recent years on the influence of TCM on VEGF. It is found that many Chinese medicines and recipes have a regulatory effect on VEGF, indicating that Chinese medicine has broad prospects as a complementary and alternative therapy, providing new treatment ideas for clinical applications and the theoretical basis for research on the mechanisms of TCM. 血管内皮生长因子是胚胎发育、骨骼生长、生殖功能等过程中生理性血管生成的共同调节因子，同时也参与一系列的病理变化。中医有2000多年的历史，在临床上得到了广泛的应用，但对中医机制的探索才刚刚开始。本文总结了近年来中医药干预血管内皮生长因子的相关研究，发现许多中药和方剂对血管内皮生长因子具有调节作用，说明中医药作为补充和替代疗法具有广阔的前景，为临床提供新的治疗思路，并为中医药的机制研究提供理论依据。 Vascular endothelial growth factor (VEGF) VEGF receptor Traditional Chinese medicine (TCM) 血管内皮生长因子 血管内皮生长因子受体 中医药 1 Introduction 1 The vascular endothelial growth factor (VEGF), is a joint regulator of physiological angiogenesis during the process of embryonic development, bone growth, and reproductive function ( Ferrara et al., 2003 Ferrara et al., 2003 ). Furthermore, it has roles in a series of pathological changes. During the history of research on the relationship between tumors and pathological angiogenesis in the past 100 years, many involved molecules have been highlighted. Senger et al. (1983) Senger et al. (1983) discovered a protein that promotes the permeability of vascular endothelial cells from guinea pig tumor cells and subsequently named it as vascular permeability factor (VPF) based on its biological effects. Ferrara and Henzel (1989) Ferrara and Henzel (1989) isolated a substance from bovine pituitary follicular cells that can promote the mitosis of vascular endothelial cells according to its target cell specificity, and named it as VEGF. Furthermore, their respective teams confirmed through gene sequence analysis that VEGF and VPF were the same molecules ( Connolly et al., 1989 Connolly et al., 1989 ; Keck et al., 1989 Keck et al., 1989 ; Leung et al., 1989 Leung et al., 1989 ). Since then, VEGF has been the subject of most in-depth studies on angiogenesis ( Ferrara, 2002 Ferrara, 2002 ). VEGF ligand proteins include VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF) ( Park et al., 1994 Park et al., 1994 ; Olofsson et al., 1996 Olofsson et al., 1996 ; Shibuya, 2003 Shibuya, 2003 ; Karkkainen et al., 2004 Karkkainen et al., 2004 ; Duong et al., 2014 Duong et al., 2014 ). Among them, VEGF-A has been the most extensively studied one. In a study on VEGF, the identified VEGF subtypes are VEGF121, VEGF165, VEGF189, and VEGF206, which are all subtypes of VEGF-A ( Ferrara et al., 2003 Ferrara et al., 2003 ). In many other articles, VEGF-A is also directly referred to as VEGF. VEGF protein receptors can be divided into receptor tyrosine kinases, neuropilins (NRPs), and heparan sulfate proteoglycans (HSPGs). Receptor tyrosine kinases include VEGF receptor-1 (VEGFR-‍‍1), VEGFR-2, and VEGFR-3, among which VEGFR-2 is currently recognized as the main receptor for angiogenesis and the enhancement of vascular permeability. NRPs are classified into NRP-1 and NRP-2 ( Chen et al., 1997 Chen et al., 1997 ; Kawasaki et al., 1999 Kawasaki et al., 1999 ). The former is preferentially localized in arteries, while the latter is expressed in veins ( Herzog et al., 2001 Herzog et al., 2001 ). HSPGs are considered to be co-receptors, enhancing the stability of the receptor complex ( Dai and Rabie, 2007 Dai and Rabie, 2007 ). This review intends to summarize the research of past five years on the influence of traditional Chinese medicine (TCM) that is relevant to the expression of VEGF proteins and receptors, and is based on disease classification. For the ease of access, we organized the recipes by mentioning the medicines and their constituents in alphabetical order according to the unified names included in the 2020 edition of Pharmacopoeia of the People's Republic of China ( Chinese Pharmacopoeia Commission, 2020 Chinese Pharmacopoeia Commission, 2020 ), as shown in Table 1 Table 1 . * This drug is not included in the Pharmacopoeia of the People's Republic of China , and hence the name in the original literature is used. ** This drug is not included in the Pharmacopoeia of the People's Republic of China , and the name in the original literature is incorrect, so we used the corresponding Latin name of the drug in the Chinese literature published by the team of Zhou et al. (2019a) Zhou et al. (2019a) and Chinese Materia Medica Commission of the National Administration of Traditional Chinese Medicine (1999) Chinese Materia Medica Commission of the National Administration of Traditional Chinese Medicine (1999) . To be continued Recipe Ingredients Buyang Huanwu Decoction Angelicae Sinensis Radix, Astragali Radix, Carthami Flos, Chuanxiong Rhizoma, Paeoniae Radix Rubra, Persicae Semen, Pheretima Xijiao Dihuang Decoction Bubali Cornu, Moutan Cortex, Paeoniae Radix Alba, Rehmanniae Radix Ginseng Yangrong Decoction Angelicae Sinensis Radix, Astragali Radix, Atractylodis Macrocephalae Rhizoma, Cinnamomi Cortex, Citri Reticulatae Pericarpium, Ginseng Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle, Jujubae Fructus, Paeoniae Radix Alba, Polygalae Radix, Poria, Rehmanniae Radix Preparata, Schisandrae Chinensis Fructus, Zingiberis Rhizoma Recens Houshiheisan Alumen, Angelicae Sinensis Radix, Asari Radix et Rhizoma, Atractylodis Macrocephalae Rhizoma, Chrysanthemi Flos, Chuanxiong Rhizoma, Cinnamomi Ramulus, Ginseng Radix et Rhizoma, Ostreae Concha, Platycodonis Radix, Poria, Saposhnikoviae Radix, Scutellariae Radix, Zingiberis Rhizoma Tianqi Jiangtang Capsule Astragali Radix, Coptidis Rhizoma, Corni Fructus, Dendrobii Caulis, Ginseng Radix et Rhizoma, Galla Chinensis, Ligustri Lucidi Fructus, Lycii Cortex, Trichosanthis Radix, Ecliptae Herba Shexiang Baoxin Pill Artificial Moschus, Borneolum Syntheticum, Bovis Calculus Artifactus, Bufonis Venenum, Cinnamomi Cortex, Ginseng Radix et Rhizoma, Styrax Danggui Buxue Decoction Angelicae Sinensis Radix, Astragali Radix Xiaoyaosan Angelicae Sinensis Radix, Atractylodis Macrocephalae Rhizoma, Bupleuri Radix, Glycyrrhizae Radix et Rhizoma, Paeoniae Radix Alba, Poria Weichang'an Formula Actinidia arguta (Siebold and Zucc.) Planch. ex Miq. [Actinidiaceae] * , Atractylodis Macrocephalae Rhizoma, Citri Reticulatae Pericarpium, Poria, Prunellae Spica, Pseudostellariae Radix, Sargentodoxae Caulis, Smilacis Chinae Rhizoma Sinisan Aurantii Fructus Immaturus, Bupleuri Radix, Glycyrrhizae Radix et Rhizoma, Paeoniae Radix Alba Yu Ping Feng San Astragali Radix, Atractylodis Macrocephalae Rhizoma, Saposhnikoviae Radix Jiedu Recipe Cremastrae Pseudobulbus/Pleiones Pseudobulbus, Galli Gigerii Endothelium Corneum, Salvia Chinensis * , Valvate Actinidia Root * Soufeng Yuchuan Decoction Armeniacae Semen Amarum, Bombyx Batryticatus, Carthami Flos, Chloriti Lapis, Cicadae Periostracum, Codonopsis Radix, Crataegi Fructus, Ephedrae Herba, Eriobotryae Folium, Glycyrrhizae Radix et Rhizoma, Orange Collaterals * , Pheretima, Raphani Semen Xuanbai Chengqi Decoction Armeniacae Semen Amarum, Gypsum Fibrosum, Rhei Radix et Rhizoma, Trichosanthis Pericarpium Yangfei Huoxue Decoction Astragali Radix, Chuanxiong Rhizoma, Euonymus Alatus * , Glehniae Radix, Polygoni Cuspidati Rhizoma et Radix, Salviae Miltiorrhizae Radix et Rhizoma, Schisandrae Chinensis Fructus ELeng Capsule Angelicae Sinensis Radix, Aurantii Fructus, Curcumae Rhizoma, Hirudo, Paeoniae Radix Rubra, Salviae Miltiorrhizae Radix et Rhizoma, Sparganii Rhizoma, Trionycis Carapax Huayu Xiaozheng Decoction Morindae Officinalis Radix, Coicis Semen, Corydalis Rhizoma, Dianthi Herba, Draconis Sanguis, Fritillariae Thunbergii Bulbus, Hirudo, Notoginseng Radix et Rhizoma, Polygoni Avicularis Herba, Prunellae Spica, Rhei Radix et Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Typhae Pollen Xiao Liu Fang Cervi Cornu, Codonopsis Radix, Curcumae Rhizoma, Eupolyphaga Steleophaga, Hirudo, Ficus pumila L. ** , Salvia Chinensis * , Smilacis Chinae Rhizoma, Trionycis Carapax, Vaccariae Semen, Zingiberis Thizoma Preparatum Bushen Yutai Recipe Angelicae Sinensis Radix, Astragali Radix, Codonopsis Radix, Cuscutae Semen, Cyperi Rhizoma, Ligustri Lucidi Fructus, Ophiopogonis Radix, Psoraleae Fructus, Rehmanniae Radix Praeparata, Salviae Miltiorrhizae Radix et Rhizoma Wenshen Yangxue Decoction Achyranthis Bidentatae Radix, Angelicae Sinensis Radix, Asari Radix et Rhizoma, Aucklandiae Radix, Bupleuri Radix, Carthami Flos, Cervi Cornu, Chuanxiong Rhizoma, Cistanches Herba, Corni Fructus, Cuscutae Semen, Cyperi Rhizoma, Epimedii Folium, Leonuri Herba, Lycii Fructus, Lycopi Herba, Notopterygii Rhizoma et Radix, Paeoniae Radix Rubra, Rehmanniae Radix Praeparata, Rubi Fructus, Salviae Miltiorrhizae Radix et Rhizoma, Spatholobi Caulis, Typhae Pollen 2 Nervous system diseases 1 In recent years, cerebrovascular disease has become a popular field within VEGF-related research. Among the listed preparations, the classic Chinese recipe Buyang Huanwu Decoction was confirmed by many researchers to promote the expression of VEGF and VEGFR in middle cerebral artery occlusion (MCAO) in rats ( Cai et al., 2007 Cai et al., 2007 ; Zheng et al., 2018 Zheng et al., 2018 ). Zhan et al. (2019) Zhan et al. (2019) treated MCAO rats with Xiaoshuan enteric-soluble capsules (a novel formulation of the Buyang Huanwu Decoction) and found that the number of cluster of differentiation 31-positive (CD31 + ) and nerve/glial antigen 2 (NG2)/CD31 + cells in the peripheral infarct cortex increased significantly in the combined treatment group of TCM and the enriched environment (EE) treatment group. Compared with the monotherapy group, the messenger RNA (mRNA) expression levels of VEGF , angiopoietin-‍‍1 ( Ang-‍‍1‍ ), Ang-2 , and axon guidance molecules were significantly increased; increased protein expression has its own advantages. It was suggested that the combined use of Xiaoshuan enteric-coated capsules and EE is beneficial to neurovascular reorganization by enhancing neurogenesis and angiogenesis, thus promoting recovery after ischemic stroke. In a further study on the therapeutic mechanism of Buyang Huanwu Decoction in stroke patients, Chen et al. (2019) Chen et al. (2019) found that Paeoniae Radix Alba can inhibit the activation of hypoxia inducible factor-1α (HIF-1α)/VEGF pathway in rats with cerebral ischemia-reperfusion injury, stabilize β‍-epithelial sodium channel (β‍-‍ENaC) ion channels, maintain the integrity and stability of the blood–brain barrier, and thereby treat ischemic stroke. In addition to the Buyang Huanwu Decoction, other TCM recipes have also proved effective in the treatment of MCAO. Xijiao Dihuang Decoction can reduce the expression of interleukin-6 (IL-6) and IL-1β in MCAO rats, inhibit the activation of nuclear factor-‍κB (NF-‍κB), and upregulate the expression of neurogenesis factors (brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF)) and angiogenesis factors (VEGF, basic fibroblast growth factor (bFGF), CD34). Consequently, it can reduce inflammation, reduce cell apoptosis, protect brain nerves, promote vascular regeneration, reduce infarct volume, and improve motor function after ischemia ( Fei et al., 2018 Fei et al., 2018 ). Ginseng Yangrong Decoction and Astragaloside IV can activate the HIF/VEGF/Notch pathway through microRNA-210 (miRNA-210), promote VEGF expression, and induce vascular endothelial cell migration and arteriovenous differentiation, thereby exerting the protective effect on angiogenesis after cerebral ischemic injury ( Liang et al., 2020 Liang et al., 2020 , 2021 2021 ). Houshiheisan and Gastrodin have also been proven to significantly upregulate VEGF and VEGFR, protect blood vessels and neurons, and promote vascular remodeling in the ischemic hemisphere ( Wang et al., 2018 Wang et al., 2018 ; Xiang et al., 2019 Xiang et al., 2019 ). Moreover, VEGF has been found to exhibit neuroprotective effects, with its potential mechanism being the stimulation of axon growth, Schwann cell proliferation, and nerve perfusion ( de Almodovar et al., 2009 de Almodovar et al., 2009 ). Han et al. (2019) Han et al. (2019) confirmed through in vitro experiments that the Tianqi Jiangtang Capsule can promote the survival of hippocampus neural stem cells, the replication and differentiation of newborn neurons and astrocytes, and reduce the degeneration and necrosis of nerve cells by upregulating the expression of VEGF and BDNF. However, the relationship between VEGF and the formation of nerve cells still needs more experimental data to confirm. Herein, we summarize the studies related to TCM, listing the therapeutic targets and functions of preparations in Table 2 Table 2 for easy reading. The sections hereinafter will also be organized in corresponding tables at the end of each section. VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; Ang: angiopoietin; NG2: nerve/glial antigen 2; CD: cluster of differentiation; HIF: hypoxia inducible factor; bFGF: basic fibroblast growth factor; BDNF: brain-derived neurotrophic factor; GDNF: glial cell-derived neurotrophic factor; IL: interleukin; miRNA: microRNA; β-ENaC: β-epithelial sodium channel. Medicine Therapeutic target Function Buyang Huanwu Decoction Angiogenesis (VEGF, VEGFR, Ang-1, Ang-2, CD31 + , NG2/CD31 + ) Pathway (HIF-1α/VEGF) Promotes neurovascular recombination; stabilizes β-ENaC ion channels; maintains the integrity and stability of the blood-brain barrier Xijiao Dihuang Decoction Angiogenesis (VEGF, bFGF, CD34) Neurogenesis (BDNF, GDNF) Inflammatory (IL-6, IL-1β) Reduces inflammation; protects cerebral nerves; promotes angiogenesis Ginseng Yangrong Decoction and Astragaloside IV Genetic material (miRNA-210) Angiogenesis (VEGF) Pathway (HIF/VEGF/Notch) Induces endothelial cell migration and arteriovenous differentiation Houshiheisan and Gastrodin Angiogenesis (VEGF, VEGFR) Protects blood vessels and neurons; promotes vascular hemispherical reconstruction Tianqi Jiangtang Capsule Angiogenesis (VEGF) Neurogenesis (BDNF) Promotes the survival of hippocampal neural stem cells; promotes the replication and differentiation of newborn neurons and astrocytes 3 Circulatory system diseases 1 To date, most research on circulatory diseases has focused on ischemic heart disease. Promoting VEGF has shown great potential in the treatment of coronary heart disease by regulating angiogenesis, lymphangiogenesis, inflammation, cell apoptosis, redox reactions, fibrogenesis, and lipid metabolism ( Zhou et al., 2021 Zhou et al., 2021 ). A clinical observation involving 248 patients with coronary artery disease and 48 healthy controls found that the serum VEGF levels of patients with acute coronary syndrome (ACS) and stable angina pectoris (SAP) were higher than those of the healthy group. Moreover, the VEGF levels of patients with ACS were higher than those with SAP, which contradicts the results of multiple observational studies conducted in the past ( Konopka et al., 2013 Konopka et al., 2013 ; Ramos et al., 2014 Ramos et al., 2014 ). This may be because unstable atherosclerotic plaques cause inflammation and induce the expression and release of VEGF in cardiomyocytes. It is worthwhile to further study the mechanism of VEGF in cardiovascular diseases ( Huang et al., 2020 Huang et al., 2020 ). A meta-analysis showed that Shexiang Baoxin Pills can significantly promote the expression of VEGF in experimental animals with coronary heart disease while reducing the area of myocardial infarction, increasing the count of microvessels, and exerting myocardial protection ( Zhang KJ et al., 2017 Zhang KJ et al., 2017 ). Hu et al. (2018) Hu et al. (2018) found that Danggui Buxue Decoction can significantly increase the mRNA and protein expression levels of VEGF, VEGFR1, and VEGFR2 in the myocardial tissue of rats with myocardial infarction, while it reduces soluble VEGFR1/2, increases the expression of membrane VEGFR1/2, and improves heart function. The isochlorogenic acid A and luteolin-7- O -glucuronide extracted from Ixeris sonchifolia Hance can bind to the ligand-free VEGFR2 to protect cardiomyocytes from oxidative stress, which is beneficial to the treatment of coronary heart disease ( Wang et al., 2020 Wang et al., 2020 ). Therapeutic targets and effects of each preparation in this section are shown in Table 3 Table 3 . VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor. Medicine Therapeutic target Function Shexiang Baoxin Pill Angiogenesis (VEGF) Promotes microvascular formation Danggui Buxue Decoction Angiogenesis (VEGF, VEGFR1, and VEGFR2) Promotes angiogenesis Isochlorogenic acid A, luteolin-7- O -glucuronide Angiogenesis (ligand-free VEGFR2) Protects cardiomyocytes from redox reactions 4 Digestive system diseases 1 Regarding gastrointestinal diseases, tumors have been the focus of VEGF-related research. Ginsenosides are considered to have anti-cancer effects ( Kim et al., 2014 Kim et al., 2014 ; Tian et al., 2016 Tian et al., 2016 ; Zhou et al., 2016 Zhou et al., 2016 ; Sun et al., 2017 Sun et al., 2017 ; Liu et al., 2021 Liu et al., 2021 ). Using an orthotopic mouse model of human gastric cancer, Dai et al. (2017) Dai et al. (2017) found that the VEGFR-3 antibody coupled to ginsenoside Rg3 nanoemulsion significantly inhibited the expression of VEGF-C, VEGF-D, and VEGFR3, targeted the inhibition of lymphatic vessel formation, and inhibited tumor growth and metastasis. Zhao et al. (2020) Zhao et al. (2020) established that Xiaoyaosan could inhibit the expression of VEGF in colon cancer rats ( P < 0.001), and attenuate the invasion and metastasis of colon cancer cells induced by chronic stress. Pan et al. (2020) Pan et al. (2020) indicated that Weichang'an Formula can inhibit the mRNA and protein expression of VEGF-A and VEGFR-1 in a colon cancer mouse model. The expression of VEGFR-1 in the Weichang'an Formula and bevacizumab combined treatment group was significantly lower than that in the bevacizumab group, suggesting that Weichang'an Formula can not only inhibit the angiogenesis of colon cancer but also enhance the anti-angiogenesis effect of bevacizumab at the VEGFR level, making up for the deficiency of bevacizumab. Through experiments with liver fibrosis in mice, Wang et al. (2021) Wang et al. (2021) indicated that Si-Ni-San had a regulatory effect on liver microvasculature. The expression levels of VEGF, VEGFR1, and VEGFR2 in the treatment group were significantly lower than those in the model group ( P < 0.01). It may be that the core components of Si-Ni-San, such as glycyrrhizic acid, saikosaponin A, paeoniflorin, and naringin, played a role. Yuan et al. (2019) Yuan et al. (2019) reported that the microvessel density (MVD) and VEGF levels of liver cancer mice treated with Yu Ping Feng San were significantly reduced, as it could downregulate the expression of the thymic stromal lymphopoietin (TSLP)‍-signal transducer and activator of transcription 3 (STAT3) signaling pathway and exert an anti-angiogenesis effect. Lin et al. (2021) Lin et al. (2021) reported that the Jiedu Recipe can reduce the expression of various inflammatory cytokines after arterial chemoembolization in patients with hepatocellular carcinoma, significantly lower the level of VEGF, and inhibit the IL-8/HIF-1α/phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways, thus blocking hypoxia-induced angiogenesis and improving the tumor hypoxia microenvironment. In addition to the TCM recipes, the TCM monomers astragaloside IV and curcumin have also been confirmed to have a synergistic inhibitory effect on the angiogenic factors VEGF, FGF-2, matrix metalloproteinase ‍ ‍2 (MMP-2), hepatocyte growth factor (HGF), and thrombosis-related factors (tissue factor (TF) and coagulation factor VII (FVII)) in the treatment of liver cancer nude mice ( Zhang S et al., 2017 Zhang S et al., 2017 ). Angelica lactone A can downregulate the expression of CD31, VEGF, and VEGFR2, and alleviate the capillarization of hepatic sinusoids, thereby inhibiting liver fibrosis ( Zhao et al., 2017 Zhao et al., 2017 ). Therapeutic targets and effects of each preparation in this section are shown in Table 4 Table 4 . VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; TSLP: thymic stromal lymphopoietin; STAT3: signal transducer and activator of transcription 3; IL: interleukin; HIF: hypoxia inducible factor; PI3K: phosphoinositide-3-kinase; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; FGF: fibroblast growth factor; MMP: matrix metalloproteinase; HGF: hepatocyte growth factor; TF: tissue factor; FVII: factor VII; CD: cluster of differentiation. Medicine Therapeutic target Function VEGFR-3 antibody coupled to ginsenoside Rg3 nanoemulsion Angiogenesis (VEGF-C, VEGF-D, VEGFR3) Inhibits lymphatic formation Xiaoyaosan Angiogenesis (VEGF) Attenuates the invasion and metastasis of colon cancer cells induced by chronic stress Weichang'an Formula Angiogenesis (VEGF-A, VEGFR1) Inhibits angiogenesis Si-Ni-San Angiogenesis (VEGF, VEGFR1, VEGFR2) Regulates liver microvessels Yu Ping Feng San Angiogenesis (VEGF) Pathway (TSLP-STAT3) Inhibits angiogenesis Jiedu Recipe Angiogenesis (VEGF) Pathway (IL-8/HIF-1α/PI3K, MAPK/ERK) Inhibits hypoxia-induced angiogenesis Astragaloside IV, curcumin Angiogenesis (VEGF, FGF-2) Bio-enzyme (MMP-2, HGF) Thrombosis-related factors (TF, FVII) Inhibits angiogenesis Angelica lactone A Angiogenesis (VEGF, VEGFR2, CD31) Reduces hepatic sinusoidal capillarization 5 Respiratory diseases 1 The mechanism that involves VEGF in the lung is complex. Normal lung development depends on the expression of VEGF, which is the highest among normal tissues ( Kaner et al., 2000 Kaner et al., 2000 ). The increase in bronchial blood vessels can induce the transport of inflammatory cells, as well as the exudation and penetration of mediators, and may also lead to airway hyperresponsiveness by increasing the quality of airway smooth muscle. On the other hand, the increased expression of VEGF in the distal airways and alveoli may protect from emphysema. Therefore, the role of VEGF in the lungs may vary by location and timing ( Papaioannou et al., 2006 Papaioannou et al., 2006 ). However, in recent years, relevant experiments with TCM have not revealed specific results for different parts. Yan et al. (2020) Yan et al. (2020) reported that Soufeng Yuchuan Decoction significantly reduced the expression of VEGF and transforming growth factor-β1 (TGF-β1) in asthmatic rats, and inhibited airway remodeling in asthmatic patients. Through experiments in rats with acute lung injury, Zhu et al. (2021) Zhu et al. (2021) indicated that Xuanbai Chengqi Decoction can downregulate the expression of VEGF protein, inhibit bronchoalveolar vascular permeability, and reduce pulmonary edema. Liu et al. (2019) Liu et al. (2019) reported that Yangfei Huoxue Decoction can inhibit the expression of VEGF and IL-1β in rats with pulmonary fibrosis, and thus regulate the inflammatory immune response. Therapeutic targets and effects of each preparation in this section are shown in Table 5 Table 5 . VEGF: vascular endothelial growth factor; TGF-β1: transforming growth factor-β1; IL: interleukin. Medicine Therapeutic target Function Soufeng Yuchuan Decoction Angiogenesis (VEGF) Profibrotic growth factor (TGF-β1) Inhibits airway remodeling Xuanbai Chengqi Decoction Angiogenesis (VEGF) Inhibits bronchoalveolar vascular permeability Yangfei Huoxue Decoction Angiogenesis (VEGF) Inflammatory (IL-1β) Regulates immune inflammatory response 6 Gynecological diseases 1 Endometriosis is generally considered to be the result of retrograde menstrual blood flow. The detached endometrium is deposited in the peritoneal cavity. Angiogenesis is essential for the growth of the detached endometrium in other tissues ( Donnez et al., 1998 Donnez et al., 1998 ). Zheng WL et al. (2021) Zheng WL et al. (2021) treated rats with endometriosis with ELeng Capsule and found that MVD and the expression of VEGF, bFGF, and platelet-derived growth factor (PDGF) in the lesion site of the treatment group were lower than those in the control group ( P < 0.01), thus inhibiting the formation of ectopic vessels. In addition, Huayu Xiaozheng Decoction was proven to have similar effects in inhibiting ectopic angiogenesis ( Chen and Gong, 2017 Chen and Gong, 2017 ). Zhou et al. (2019b) Zhou et al. (2019b) found through in vitro experiments that Xiao Liu Fang could reduce the expression of VEGF, MMP-9, cyclooxygenase-2 (COX-2) and intercellular adhesion molecule 1 (ICAM-1), reduce the separation between cells of the same type and adhesion between cells of different types, and reduce angiogenesis, thus successfully treating endometriosis. Infertility has plagued contemporary young people for a long time, and it has been confirmed that the VEGF-A concentration in fertile women is generally significantly higher than that in unexplained infertile women ( Hannan et al., 2011 Hannan et al., 2011 ). Thus, treatment targeting VEGF may be of great help in achieving pregnancy. Jiang et al. (2020) Jiang et al. (2020) used the Bushen Yutai Recipe to treat in vitro fertilization patients, showing significantly higher expression of VEGF gene in exfoliated endometrial cells than in the control group. Xin et al. (2018) Xin et al. (2018) reported that Wenshen Yangxue Decoction can increase the expression of MVD, VEGF, Ang-1, and Ang-2, suggesting that TCM may increase endometrial blood flow, promote endometrial angiogenesis, and improve endometrial receptivity, which aids the treatment of infertility. Therapeutic targets and effects of each preparation in this section are shown in Table 6 Table 6 . VEGF: vascular endothelial growth factor; bFGF: basic fibroblast growth factor; PDGF: platelet-derived growth factor; MMP-9: matrix metallopeptidase 9; COX-2: cyclooxygenase-2; ICAM-1: intercellular adhesion molecule 1; MVD: microvessel density; Ang: angiopoietin. Medicine Therapeutic target Function ELeng Capsule, Huayu Xiaozheng Decoction Angiogenesis (VEGF, bFGF, PDGF) Inhibits the formation of ectopic blood vessels Xiao Liu Fang Angiogenesis (VEGF) Bio-enzyme (MMP-9, COX-2) Adhesion molecule (ICAM-1) Reduces the separation of the same type of cells; reduces the adhesion between different types of cells; reduces angiogenesis Bushen Yutai Recipe Angiogenesis (VEGF) Induces angiogenesis Wenshen Yangxue Decoction Angiogenesis (MVD, VEGF, Ang-1, Ang-2) Increases endometrial blood flow; promotes endometrial angiogenesis 7 Other diseases and related research 1 Taohe Chengqi Decoction can inhibit the expression of PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and HIF-1α/VEGF signaling pathways, thereby regulating the inflammatory process and epithelial‍–‍mesenchymal transition, which in turn reduces the excessive deposition of abnormal extracellular matrix and inhibits the progression of renal fibrosis ( Zhou et al., 2020 Zhou et al., 2020 ). Fuxin Granules can inhibit the expression of VEGFA and VEGFR2 in diabetic nephropathy mice and exert a renal protection effect, but the more specific mechanism of action needs to be further explored ( Zheng WW et al., 2021 Zheng WW et al., 2021 ). Shikonin can increase the levels of VEGF, bFGF, TGF-β, and PDGF in rabbits with skin injury ( P < 0.05) and enhance the activation of TGF-β1/Smad signaling pathway, thereby promoting the proliferation of fibroblasts and subsequently the healing of skin ulcer ( Yang et al., 2021 Yang et al., 2021 ). The mixed extracts of Angelica Dahurica and Rhubarb can upregulate the expression of VEGF and inducible nitric oxide synthase (iNOS) in diabetic rats and inhibit the NF‍-‍κB pathway, which can improve inflammation and promote wound healing ( Chao et al., 2021 Chao et al., 2021 ). Matrine can downregulate the expression of IL-1β, interferon-‍γ, VEGF, PlGF, HIF-1α, Ang-1, Ang-2, Tie-2, and phosphorylated AKT in collagen-induced arthritis rats, suggesting its ability to regulate the HIF-VEGF-Ang axis and inhibit the PI3K/AKT pathway ( Ao et al., 2022 Ao et al., 2022 ). The ultimate effect is the reduction of new blood vessel formation and improvement of rheumatoid arthritis symptoms. Kuchta et al. (2017) Kuchta et al. (2017) conducted in vitro experiments and confirmed that celastrol can effectively inhibit the secretion of VEGF in PC-3 cells and target the inhibition of VEGF/VEGFR2 signaling pathway, thus inhibiting angiogenesis, exerting anti-tumor activity, and preventing prostate cancer bone metastasis. 8 Discussion 1 TCM is a treasure of Chinese civilization and still occupies a crucial position in China's medical system. The philosophy of TCM is focused on treating people as a whole, analyzing diseases by their symptoms, and prescribing remedies by TCM types. On the other hand, the Western approach within China has put more emphasis on extracting effective chemical components from a single herb. Nowadays, TCM also focuses on extracting natural products with biological activity through modern methods and analyzing them at the cellular, molecular, and pharmacological levels, in order to discover ingredients that can supplement Western medicine: the research on TCM in China has also tended to the micro level. More and more Chinese medicine practitioners and scholars have devoted themselves to exploring the influence of TCM on molecules and cells to clarify its mechanism, in order to gain worldwide recognition. In recent years, the relevant research on the effects of TCM on VEGF has covered a wide range of content, including classic recipes, empirical recipes, and monomers. Among the Chinese medicines used, blood-activating drugs account for a large proportion. The VEGF itself is closely related to blood and blood vessels. According to the theory of Chinese medicine, it is easy to associate drugs with a blood-activating effect. To this end, Salviae Miltiorrhizae Radix et Rhizoma, Angelicae Sinensis Radix, Chuanxiong Rhizoma, etc., which have been studied more frequently, are commonly used clinical medicines in TCM. The research results for blood-activating drugs are often synchronized with TCM cognition. For example, Gao et al. (2021) Gao et al. (2021) showed in the Flik zebrafish model that Typhae Pollen could upregulate the expression of VEGF-A in vascular-deficient zebrafish and promote angiogenesis. At the same time, Carbonized Typhae Pollen could upregulate the expression of VEGF-A in zebrafish with cerebral hemorrhage and play a vascular protective effect. This result agrees with our understanding of the efficacy of TCM—Typhae Pollen is a commonly used medicine for promoting blood circulation and removing blood stasis, while Carbonized Typhae Pollen exerts a weakened blood-activating effect and enhanced hemostatic effect. The more frequently used categories of TCM are Qi-tonifying drugs, such as Ginseng Radix et Rhizoma, Astragali Radix, and Codonopsis Radix. According to the theory of TCM, most chronic diseases damage the righteous Qi and easily lead to Qi deficiency. In such cases, Qi-tonifying drugs are needed to strengthen the body to get-rid of evil spirits. The results for the compound prescription also reveal a significant regulatory effect of Qi-tonifying drugs on VEGF; however, the constituents of the prescription are complicated. To uncover the effect of specific ingredients on VEGF expression, a lot of experiments are needed. Nevertheless, studies directed to the monomers of TCM have clearly shown their beneficial effects, which constitutes a more popular research direction in the West. For example, Tanshinone IIA has been shown to inhibit the angiogenesis of human umbilical vein endothelial cells ( Wang et al., 2015 Wang et al., 2015 ; Xing et al., 2015 Xing et al., 2015 ) and endothelial progenitor cells ( Lee et al., 2017 Lee et al., 2017 ) through inhibiting the migration of VEGF. A liposome that targets PFVYLI (PFV) modified by epirubicin and Schisandrin B (encapsulated in the hydrophilic core of liposomes and the phospholipid bilayer, respectively) can downregulate the expression of VEGF, MMP-9, and vimentin (VIM), upregulate the expression of E-cadherin (E-CAD), block migration and invasion, reduce cell adhesion, destroy the mimicry channel of angiogenesis, and inhibit angiogenesis. Therefore, it has a stronger inhibitory effect on tumor metastasis than epirubicin alone ( Jing et al., 2020 Jing et al., 2020 ). Overall, the above studies have enriched the modern research direction of TCM, allowed TCM to enter the world stage of research, and suggested that TCM has the possibility of supplementing the function of artificial synthetic drugs. Furthermore, recent studies have established that VEGF is often combined with upstream, downstream, and other factors that may affect angiogenesis. Such common factors include Ang-1, Ang-2, HIF-1α, PI3K, MMP, inflammatory factors, etc., which have been proven to be linked to angiogenesis, and their mechanisms are related to hypoxia, cell survival, cell proliferation, and inflammation ( Xia et al., 2006 Xia et al., 2006 ; Wouters and Koritzinsky, 2008 Wouters and Koritzinsky, 2008 ; Kessenbrock et al., 2010 Kessenbrock et al., 2010 ; Reuter et al., 2010 Reuter et al., 2010 ; Ahluwalia and Tarnawski, 2012 Ahluwalia and Tarnawski, 2012 ; Duran et al., 2021 Duran et al., 2021 ). To facilitate the understanding of the VEGF-related factors mentioned in this review, a pathway map was prepared in Fig. 1 Fig. 1 . As seen in the figure, TCM treatments have multi-targeting nature, prompting further studies to explore the mechanisms of TCM in many areas. 9 Conclusions 1 This review summarized and discussed the research on TCM in recent years with reference to VEGF according to the classification of related diseases. The findings indicated great research potential for VEGF and angiogenesis in many disease fields. Moreover, the integration of TCM with the global mainstream research is becoming increasingly necessary. Many scholars have proved the effects of TCM on VEGF, interpreted TCM and complex recipes from a micro perspective, and opened up new ideas of development; however, there are many challenges ahead. For instance, there are numerous types of TCM, and compound prescriptions have great variation. Also, the effects of such prescriptions on cells are often complicated and multi-targeted; therefore, more research is clearly needed to comprehensively clarify the mechanisms of TCM. References Ahluwalia A , Tarnawski AS , 2012 . Critical role of hypoxia sensor-HIF-1α in VEGF gene activation . Implications for angiogenesis and tissue injury healing. Curr Med Chem , 19 ( 1 ): 90 - 97 . https://doi.org/10.2174/092986712803413944 https://doi.org/10.2174/092986712803413944 Critical role of hypoxia sensor-HIF-1α in VEGF gene activation Ao LM , Gao H , Jia LF , et al. , 2022 . Matrine inhibits synovial angiogenesis in collagen-induced arthritis rats by regulating HIF-VEGF-Ang and inhibiting the PI3K/Akt signaling pathway . Mol Immunol , 141 : 13 - 20 . https://doi.org/10.1016/j.molimm.2021.11.002 https://doi.org/10.1016/j.molimm.2021.11.002 Matrine inhibits synovial angiogenesis in collagen-induced arthritis rats by regulating HIF-VEGF-Ang and inhibiting the PI3K/Akt signaling pathway Cai GX , Liu BY , Liu W , et al. , 2007 . Buyang Huanwu Decoction can improve recovery of neurological function, reduce infarction volume, stimulate neural proliferation and modulate VEGF and Flk1 expressions in transient focal cerebral ischaemic rat brains . J Ethnopharmacol , 113 ( 2 ): 292 - 299 . https://doi.org/10.1016/j.jep.2007.06.007 https://doi.org/10.1016/j.jep.2007.06.007 Buyang Huanwu Decoction can improve recovery of neurological function, reduce infarction volume, stimulate neural proliferation and modulate VEGF and Flk1 expressions in transient focal cerebral ischaemic rat brains Chao YH , Yang WT , Li MC , et al. , 2021 . Angelica dahurica and Rheum officinale facilitated diabetic wound healing by elevating vascular endothelial growth factor . Am J Chin Med , 49 ( 6 ): 1515 - 1533 . https://doi.org/10.1142/S0192415X21500713 https://doi.org/10.1142/S0192415X21500713 Angelica dahurica and Rheum officinale facilitated diabetic wound healing by elevating vascular endothelial growth factor Chen H , Chedotal A , He ZG , et al. , 1997 . Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III . Neuron , 19 ( 3 ): 547 - 559 . https://doi.org/10.1016/s0896-6273(00)80371-2 https://doi.org/10.1016/s0896-6273(00)80371-2 Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III Chen ZZ , Gong X , 2017 . Effect of Hua Yu Xiao Zheng decoction on the expression levels of vascular endothelial growth factor and angiopoietin‑2 in rats with endometriosis . Exp Ther Med , 14 ( 6 ): 5743 - 5750 . https://doi.org/10.3892/etm.2017.5280 https://doi.org/10.3892/etm.2017.5280 Effect of Hua Yu Xiao Zheng decoction on the expression levels of vascular endothelial growth factor and angiopoietin‑2 in rats with endometriosis Chen ZZ , Gong X , Guo Q , et al. , 2019 . Bu Yang Huan Wu decoction prevents reperfusion injury following ischemic stroke in rats via inhibition of HIF-1α, VEGF and promotion β-ENaC expression . J Ethnopharmacol , 228 : 70 - 81 . https://doi.org/10.1016/j.jep.2018.09.017 https://doi.org/10.1016/j.jep.2018.09.017 Bu Yang Huan Wu decoction prevents reperfusion injury following ischemic stroke in rats via inhibition of HIF-1α, VEGF and promotion β-ENaC expression Chinese Materia Medica Commission of the National Administration of Traditional Chinese Medicine , 1999 . The Chinese Materia Medica-Part 2 . Shanghai Scientific & Technical Publishers , Shanghai , China (in Chinese) The Chinese Materia Medica-Part 2 Chinese Pharmacopoeia Commission , 2020 . Pharmacopoeia of the People’s Republic of China (Part 1). China Medical Science Press, Beijing, China (in Chinese) . Pharmacopoeia of the People’s Republic of China (Part 1). China Medical Science Press, Beijing, China Connolly DT , Olander JV , Heuvelman D , et al. , 1989 . Human vascular permeability factor: isolation from U937 cells . J Biol Chem , 264 ( 33 ): 20017 - 20024 . https://doi.org/10.1016/S0021-9258(19)47212-8 https://doi.org/10.1016/S0021-9258(19)47212-8 Human vascular permeability factor: isolation from U937 cells Dai J , Rabie ABM , 2007 . VEGF: an essential mediator of both angiogenesis and endochondral ossification . J Dent Res , 86 ( 10 ): 937 - 950 . https://doi.org/10.1177/154405910708601006 https://doi.org/10.1177/154405910708601006 VEGF: an essential mediator of both angiogenesis and endochondral ossification Dai XJ , Liu DM , Liu MX , et al. , 2017 . Anti-metastatic efficacy of traditional Chinese medicine (TCM) ginsenoside conjugated to a VEFGR-3 antibody on human gastric cancer in an orthotopic mouse model . Anticancer Res , 37 ( 3 ): 979 - 986 . https://doi.org/10.21873/anticanres.11407 https://doi.org/10.21873/anticanres.11407 Anti-metastatic efficacy of traditional Chinese medicine (TCM) ginsenoside conjugated to a VEFGR-3 antibody on human gastric cancer in an orthotopic mouse model de Almodovar CR , Lambrechts D , Mazzone M , et al. , 2009 . Role and therapeutic potential of VEGF in the nervous system . Physiol Rev , 89 ( 2 ): 607 - 648 . https://doi.org/10.1152/physrev.00031.2008 https://doi.org/10.1152/physrev.00031.2008 Role and therapeutic potential of VEGF in the nervous system Donnez J , Smoes P , Gillerot S , et al. , 1998 . Vascular endothelial growth factor (VEGF) in endometriosis . Hum Reprod , 13 ( 6 ): 1686 - 1690 . https://doi.org/10.1093/humrep/13.6.1686 https://doi.org/10.1093/humrep/13.6.1686 Vascular endothelial growth factor (VEGF) in endometriosis Duong T , Koltowska K , Pichol-Thievend C , et al. , 2014 . VEGFD regulates blood vascular development by modulating SOX18 activity . Blood , 123 ( 7 ): 1102 - 1112 . https://doi.org/10.1182/blood-2013-04-495432 https://doi.org/10.1182/blood-2013-04-495432 VEGFD regulates blood vascular development by modulating SOX18 activity Duran CL , Borriello L , Karagiannis GS , et al. , 2021 . Targeting Tie2 in the tumor microenvironment: from angiogenesis to dissemination . Cancers , 13 ( 22 ): 5730 . https://doi.org/10.3390/cancers13225730 https://doi.org/10.3390/cancers13225730 Targeting Tie2 in the tumor microenvironment: from angiogenesis to dissemination Fei XJ , Zhang X , Wang Q , et al. , 2018 . Xijiao Dihuang Decoction alleviates ischemic brain injury in MCAO rats by regulating inflammation, neurogenesis, and angiogenesis . Evid-Based Complement Alternat Med , 2018 : 5945128 . https://doi.org/10.1155/2018/5945128 https://doi.org/10.1155/2018/5945128 Xijiao Dihuang Decoction alleviates ischemic brain injury in MCAO rats by regulating inflammation, neurogenesis, and angiogenesis Ferrara N , 2002 . VEGF and the quest for tumour angiogenesis factors . Nat Rev Cancer , 2 ( 10 ): 795 - 803 . https://doi.org/10.1038/nrc909 https://doi.org/10.1038/nrc909 VEGF and the quest for tumour angiogenesis factors Ferrara N , Henzel WJ , 1989 . Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells . Biochem Biophys Res Commun , 161 ( 2 ): 851 - 858 . https://doi.org/10.1016/0006-291x(89)92678-8 https://doi.org/10.1016/0006-291x(89)92678-8 Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells Ferrara N , Gerber HP , Lecouter J , 2003 . The biology of VEGF and its receptors . Nat Med , 9 ( 6 ): 669 - 676 . https://doi.org/10.1038/nm0603-669 https://doi.org/10.1038/nm0603-669 The biology of VEGF and its receptors Gao ML , Ge ZP , Deng R , et al. , 2021 . Evaluation of VEGF mediated pro-angiogenic and hemostatic effects and chemical marker investigation for Typhae Pollen and its processed product . J Ethnopharmacol , 268 : 113591 . https://doi.org/10.1016/j.jep.2020.113591 https://doi.org/10.1016/j.jep.2020.113591 Evaluation of VEGF mediated pro-angiogenic and hemostatic effects and chemical marker investigation for Typhae Pollen and its processed product Han CY , Liu J , Wan F , et al. , 2019 . Effects of Tianqijiangtang capsule on survival, self-renewal and differentiation of hippocampal neural stem cells of embryonic rats cultured in high glucose medium . Am J Transl Res , 11 ( 9 ): 5560 - 5572 . Effects of Tianqijiangtang capsule on survival, self-renewal and differentiation of hippocampal neural stem cells of embryonic rats cultured in high glucose medium Hannan NJ , Paiva P , Meehan KL , et al. , 2011 . Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implant ation. Endocrinology , 152 ( 12 ): 4948 - 4956 . https://doi.org/10.1210/en.2011-1248 https://doi.org/10.1210/en.2011-1248 Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implant Herzog Y , Kalcheim C , Kahane N , et al. , 2001 . Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins . Mech Dev , 109 ( 1 ): 115 - 119 . https://doi.org/10.1016/s0925-4773(01)00518-4 https://doi.org/10.1016/s0925-4773(01)00518-4 Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins Hu GY , Yang P , Zeng Y , et al. , 2018 . Danggui Buxue decoction promotes angiogenesis by up-regulation of VEGFR 1/2 expressions and down-regulation of sVEGFR 1/2 expression in myocardial infarction rat . J Chin Med Assoc , 81 ( 1 ): 37 - 46 . https://doi.org/10.1016/j.jcma.2017.06.015 https://doi.org/10.1016/j.jcma.2017.06.015 Danggui Buxue decoction promotes angiogenesis by up-regulation of VEGFR1/2 expressions and down-regulation of sVEGFR1/2 expression in myocardial infarction rat Huang AN , Qi X , Cui YM , et al. , 2020 . Serum VEGF: diagnostic value of acute coronary syndrome from stable angina pectoris and prognostic value of coronary artery disease . Cardiol Res Pract , 2020 : 6786302 . https://doi.org/10.1155/2020/6786302 https://doi.org/10.1155/2020/6786302 Serum VEGF: diagnostic value of acute coronary syndrome from stable angina pectoris and prognostic value of coronary artery disease Jiang XM , Yan H , Zhong XF , et al. , 2020 . Effect of Bushen Yutai recipe on IVF patients subjected to mild ovarian stimulation . Front Med , 7 : 541537 . https://doi.org/10.3389/fmed.2020.541537 https://doi.org/10.3389/fmed.2020.541537 Effect of Bushen Yutai recipe on IVF patients subjected to mild ovarian stimulation Jing M , Bi XJ , Yao XM , et al. , 2020 . Enhanced antitumor efficacy using epirubicin and schisandrin B co-delivery liposomes modified with PFV via inhibiting tumor metastasis . Drug Dev Ind Pharm , 46 ( 4 ): 621 - 634 . https://doi.org/10.1080/03639045.2020.1742145 https://doi.org/10.1080/03639045.2020.1742145 Enhanced antitumor efficacy using epirubicin and schisandrin B co-delivery liposomes modified with PFV via inhibiting tumor metastasis Kaner RJ , Ladetto JV , Singh R , et al. , 2000 . Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema . Am J Respir Cell Mol , 22 ( 6 ): 657 - 664 . https://doi.org/10.1165/ajrcmb.22.6.3779 https://doi.org/10.1165/ajrcmb.22.6.3779 Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema Karkkainen MJ , Haiko P , Sainio K , et al. , 2004 . Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins . Nat Immunol , 5 ( 1 ): 74 - 80 . https://doi.org/10.1038/ni1013 https://doi.org/10.1038/ni1013 Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins Kawasaki T , Kitsukawa T , Bekku Y , et al. , 1999 . A requirement for neuropilin-1 in embryonic vessel formation . Development , 126 ( 21 ): 4895 - 4902 . https://doi.org/10.1242/dev.126.21.4895 https://doi.org/10.1242/dev.126.21.4895 A requirement for neuropilin-1 in embryonic vessel formation Keck PJ , Hauser SD , Krivi G , et al. , 1989 . Vascular permeability factor, an endothelial cell mitogen related to PDGF . Science , 246 ( 4935 ): 1309 - 1312 . https://doi.org/10.1126/science.2479987 https://doi.org/10.1126/science.2479987 Vascular permeability factor, an endothelial cell mitogen related to PDGF Kessenbrock K , Plaks V , Werb Z , 2010 . Matrix metalloproteinases: regulators of the tumor microenvironment . Cell , 141 ( 1 ): 52 - 67 . https://doi.org/10.1016/j.cell.2010.03.015 https://doi.org/10.1016/j.cell.2010.03.015 Matrix metalloproteinases: regulators of the tumor microenvironment Kim YJ , Choi WI , Jeon BN , et al. , 2014 . Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance . Toxicology , 322 : 23 - 33 . https://doi.org/10.1016/j.tox.2014.04.002 https://doi.org/10.1016/j.tox.2014.04.002 Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial-mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance Konopka A , Janas J , Piotrowski W , et al. , 2013 . Concentration of vascular endothelial growth factor in patients with acute coronary syndrome . Cytokine , 61 ( 2 ): 664 - 669 . https://doi.org/10.1016/j.cyto.2012.12.001 https://doi.org/10.1016/j.cyto.2012.12.001 Concentration of vascular endothelial growth factor in patients with acute coronary syndrome Kuchta K , Xiang Y , Huang S , et al. , 2017 . Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis . Prostate Cancer Prostatic Dis , 20 ( 2 ): 156 - 164 . https://doi.org/10.1038/pcan.2016.61 https://doi.org/10.1038/pcan.2016.61 Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis Lee HP , Liu YC , Chen PC , et al. , 2017 . Tanshinone IIA inhibits angiogenesis in human endothelial progenitor cells in vitro and in vivo . Oncotarget , 8 ( 65 ): 109217 - 109227 . https://doi.org/10.18632/oncotarget.22649 https://doi.org/10.18632/oncotarget.22649 Tanshinone IIA inhibits angiogenesis in human endothelial progenitor cells in vitro and in vivo Leung DW , Cachianes G , Kuang WJ , et al. , 1989 . Vascular endothelial growth factor is a secreted angiogenic mitogen . Science , 246 ( 4935 ): 1306 - 1309 . https://doi.org/10.1126/science.2479986 https://doi.org/10.1126/science.2479986 Vascular endothelial growth factor is a secreted angiogenic mitogen Liang C , Ni GX , Shi XL , et al. , 2020 . Astragaloside IV regulates the HIF/VEGF/Notch signaling pathway through miRNA-210 to promote angiogenesis after ischemic stroke . Restor Neurol Neurosci , 38 ( 3 ): 271 - 282 . https://doi.org/10.3233/RNN-201001 https://doi.org/10.3233/RNN-201001 Astragaloside IV regulates the HIF/VEGF/Notch signaling pathway through miRNA-210 to promote angiogenesis after ischemic stroke Liang C , Zhang T , Shi XL , et al. , 2021 . Modified Renshen Yangrong decoction enhances angiogenesis in ischemic stroke through promotion of microRNA‍‐‍210 expression by regulating the HIF/VEGF/Notch signaling pathway . Brain Behav , 11 ( 8 ): e2295 . https://doi.org/10.1002/brb3.2295 https://doi.org/10.1002/brb3.2295 Modified Renshen Yangrong decoction enhances angiogenesis in ischemic stroke through promotion of microRNA‍‐‍210 expression by regulating the HIF/VEGF/Notch signaling pathway Lin WF , Wang H , Zhong MF , et al. , 2021 . Effect and molecular mechanisms of Jiedu Recipe on hypoxia-induced angiogenesis after transcatheter arterial chemoembolization in hepatocellular carcinoma . Evid-Based Complement Alternat Med , 2021 : 6529376 . https://doi.org/10.1155/2021/6529376 https://doi.org/10.1155/2021/6529376 Effect and molecular mechanisms of Jiedu Recipe on hypoxia-induced angiogenesis after transcatheter arterial chemoembolization in hepatocellular carcinoma Liu W , Zhang SX , Ai B , et al. , 2021 . Ginsenoside Rg3 promotes cell growth through activation of mTORC1 . Front Cell Dev Biol , 9 : 730309 . https://doi.org/10.3389/fcell.2021.730309 https://doi.org/10.3389/fcell.2021.730309 Ginsenoside Rg3 promotes cell growth through activation of mTORC1 Liu X , Chen H , Su GB , et al. , 2019 . An animal research and a chemical composition analysis of a Chinese prescription for pulmonary fibrosis: Yangfei Huoxue Decoction . J Ethnopharmacol , 245 : 112126 . https://doi.org/10.1016/j.jep.2019.112126 https://doi.org/10.1016/j.jep.2019.112126 An animal research and a chemical composition analysis of a Chinese prescription for pulmonary fibrosis: Yangfei Huoxue Decoction Olofsson B , Pajusola K , Kaipainen A , et al. , 1996 . Vascular endothelial growth factor B, a novel growth factor for endothelial cells . Proc Natl Acad Sci USA , 93 ( 6 ): 2576 - 2581 . https://doi.org/10.1073/pnas.93.6.2576 https://doi.org/10.1073/pnas.93.6.2576 Vascular endothelial growth factor B, a novel growth factor for endothelial cells Pan CF , Zhang X , Wang JW , et al. , 2020 . Weichang’an formula inhibits tumor growth in combination with bevacizumab in a murine model of colon cancer—making up for the deficiency of Bevacizumab by inhibiting VEGFR-1 . Front Pharmacol , 11 : 512598 . https://doi.org/10.3389/fphar.2020.512598 https://doi.org/10.3389/fphar.2020.512598 Weichang’an formula inhibits tumor growth in combination with bevacizumab in a murine model of colon cancer—making up for the deficiency of Bevacizumab by inhibiting VEGFR-1 Papaioannou AI , Kostikas K , Kollia P , et al. , 2006 . Clinical implications for vascular endothelial growth factor in the lung: friend or foe? Respir Res , 7 : 128 . https://doi.org/10.1186/1465-9921-7-128 https://doi.org/10.1186/1465-9921-7-128 Clinical implications for vascular endothelial growth factor in the lung: friend or foe? Park JE , Chen HH , Winer J , et al. , 1994 . Placenta growth factor . Potentiation of vascular endothelial growth factor bioactivity , in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem, 269 ( 41 ): 25646 - 25654 . https://doi.org/10.1016/S0021-9258(18)47298-5 https://doi.org/10.1016/S0021-9258(18)47298-5 Placenta growth factor Ramos C , Napoleão P , Selas M , et al. , 2014 . Prognostic value of VEGF in patients submitted to percutaneous coronary intervention . Dis Markers , 2014 : 135357 . https://doi.org/10.1155/2014/135357 https://doi.org/10.1155/2014/135357 Prognostic value of VEGF in patients submitted to percutaneous coronary intervention Reuter S , Gupta SC , Chaturvedi MM , et al. , 2010 . Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med , 49 ( 11 ): 1603 - 1616 . https://doi.org/10.1016/j.freeradbiomed.2010.09.006 https://doi.org/10.1016/j.freeradbiomed.2010.09.006 Oxidative stress, inflammation, and cancer: how are they linked? Senger DR , Galli SJ , Dvorak AM , et al. , 1983 . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid . Science , 219 ( 4587 ): 983 - 985 . https://doi.org/10.1126/science.6823562 https://doi.org/10.1126/science.6823562 Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid Shibuya M , 2003 . Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E . Cancer Sci , 94 ( 9 ): 751 - 756 . https://doi.org/10.1111/j.1349-7006.2003.tb01514.x https://doi.org/10.1111/j.1349-7006.2003.tb01514.x Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E Sun MY , Ye Y , Xiao L , et al. , 2017 . Anticancer effects of ginsenoside Rg3 (Review) . Int J Mol Med , 39 ( 3 ):‍ 507 - 518 . https://doi.org/10.3892/ijmm.2017.2857 https://doi.org/10.3892/ijmm.2017.2857 Anticancer effects of ginsenoside Rg3 (Review) Tian LL , Shen DC , Li XD , et al. , 2016 . Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4 . Oncotarget , 7 ( 2 ): 1619 - 1632 . https://doi.org/10.18632/oncotarget.6451 https://doi.org/10.18632/oncotarget.6451 Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4 Wang SL , Tang C , Zhao H , et al. , 2021 . Network pharmacological analysis and experimental validation of the mechanisms of action of Si-Ni-San against liver fibrosis . Front Pharmacol , 12 : 656115 . https://doi.org/10.3389/fphar.2021.656115 https://doi.org/10.3389/fphar.2021.656115 Network pharmacological analysis and experimental validation of the mechanisms of action of Si-Ni-San against liver fibrosis Wang SQ , Nan YN , Zhu WH , et al. , 2018 . Gastrodin improves the neurological score in MCAO rats by inhibiting inflammation and apoptosis, promoting revascularization . Int J Clin Exp Pathol , 11 ( 11 ): 5343 - 5350 . Gastrodin improves the neurological score in MCAO rats by inhibiting inflammation and apoptosis, promoting revascularization Wang X , Li Y , Chen ML , et al. , 2020 . Stepwise rapid tracking strategy to identify active molecules from Ixeris sonchifolia Hance based on “‘affinity mass spectrometry-atomic force microscopy imaging’” technology . Talanta , 217 : 121031 . https://doi.org/10.1016/j.talanta.2020.121031 https://doi.org/10.1016/j.talanta.2020.121031 Stepwise rapid tracking strategy to identify active molecules from Ixeris sonchifolia Hance based on “‘affinity mass spectrometry-atomic force microscopy imaging’” technology Wang Y , Li JX , Wang YQ , et al. , 2015 . Tanshinone I inhibits tumor angiogenesis by reducing STAT3 phosphorylation at TYR705 and hypoxia-induced HIF-1α accumulation in both endothelial and tumor cells . Oncotarget , 6 ( 18 ): 16031 - 16042 . https://doi.org/10.18632/oncotarget.3648 https://doi.org/10.18632/oncotarget.3648 Tanshinone I inhibits tumor angiogenesis by reducing STAT3 phosphorylation at TYR705 and hypoxia-induced HIF-1α accumulation in both endothelial and tumor cells Wouters BG , Koritzinsky M , 2008 . Hypoxia signalling through mTOR and the unfolded protein response in cancer . Nat Rev Cancer , 8 ( 11 ): 851 - 864 . https://doi.org/10.1038/nrc2501 https://doi.org/10.1038/nrc2501 Hypoxia signalling through mTOR and the unfolded protein response in cancer Xia C , Meng Q , Cao ZX , et al. , 2006 . Regulation of angiogenesis and tumor growth by p110 Alpha and AKT1 via VEGF expression . J Cell Physiol , 209 ( 1 ): 56 - 66 . https://doi.org/10.1002/jcp.20707 https://doi.org/10.1002/jcp.20707 Regulation of angiogenesis and tumor growth by p110 Alpha and AKT1 via VEGF expression Xiang YY , Yao XQ , Wang X , et al. , 2019 . Houshiheisan promotes angiogenesis via HIF-1α/VEGF and SDF-1/CXCR4 pathways: in vivo and in vitro . Biosci Rep , 39 ( 10 ): BSR20191006 . https://doi.org/10.1042/BSR20191006 https://doi.org/10.1042/BSR20191006 Houshiheisan promotes angiogenesis via HIF-1α/VEGF and SDF-1/CXCR4 pathways: in vivo and invitro Xin MW , He JQ , Yang W , et al. , 2018 . Wenshen Yangxue decoction improves endometrial receptivity recovery and promotes endometrial angiogenesis in a rat model . Pharm Biol , 56 ( 1 ): 573 - 579 . https://doi.org/10.1080/13880209.2018.1510973 https://doi.org/10.1080/13880209.2018.1510973 Wenshen Yangxue decoction improves endometrial receptivity recovery and promotes endometrial angiogenesis in a rat model Xing YY , Tu JJ , Zheng LF , et al. , 2015 . Anti-angiogenic effect of tanshinone IIA involves inhibition of the VEGF/VEGFR2 pathway in vascular endothelial cells . Oncol Rep , 33 ( 1 ): 163 - 170 . https://doi.org/10.3892/or.2014.3592 https://doi.org/10.3892/or.2014.3592 Anti-angiogenic effect of tanshinone IIA involves inhibition of the VEGF/VEGFR2 pathway in vascular endothelial cells Yan YB , Liu LL , Dou ZY , et al. , 2020 . Soufeng Yuchuan decoction mitigates the ovalbumin-induced lung damage in a rat model of asthma . Biomed Pharmacother , 125 : 109933 . https://doi.org/10.1016/j.biopha.2020.109933 https://doi.org/10.1016/j.biopha.2020.109933 Soufeng Yuchuan decoction mitigates the ovalbumin-induced lung damage in a rat model of asthma Yang X , Fan WJ , Huang RY , et al. , 2021 . β‍-Acetoxyisovaleryl alkannin (AAN-II) from Alkanna tinctoria promotes the healing of pressure-induced venous ulcers in a rabbit model through the activation of TGF-‍β/Smad3 signaling . Cell Mol Biol Lett , 26 : 35 . https://doi.org/10.1186/s11658-021-00278-5 https://doi.org/10.1186/s11658-021-00278-5 β‍-Acetoxyisovaleryl alkannin (AAN-II) from Alkanna tinctoria promotes the healing of pressure-induced venous ulcers in a rabbit model through the activation of TGF-‍β/Smad3 signaling Yuan Q , Yao F , Zhou L , et al. , 2019 . Yu Ping Feng San exert anti-angiogenesis effects through the inhibition of TSLP-STAT3 signaling pathways in hepatocellular carcinoma . Evid-Based Complement Alternat Med , 2019 : 1947156 . https://doi.org/10.1155/2019/1947156 https://doi.org/10.1155/2019/1947156 Yu Ping Feng San exert anti-angiogenesis effects through the inhibition of TSLP-STAT3 signaling pathways in hepatocellular carcinoma Zhan Y , Li MZ , Yang L , et al. , 2019 . An MRI study of neurovascular restorative after combination treatment with Xiaoshuan enteric-coated capsule and enriched environment in rats after stroke . Front Neurosci , 13 : 701 . https://doi.org/10.3389/fnins.2019.00701 https://doi.org/10.3389/fnins.2019.00701 An MRI study of neurovascular restorative after combination treatment with Xiaoshuan enteric-coated capsule and enriched environment in rats after stroke Zhang KJ , Zhu JZ , Bao XY , et al. , 2017 . Shexiang Baoxin Pills for coronary heart disease in animal models: preclinical evidence and promoting angiogenesis mechanism . Front Pharmacol , 8 : 404 . https://doi.org/10.3389/fphar.2017.00404 https://doi.org/10.3389/fphar.2017.00404 Shexiang Baoxin Pills for coronary heart disease in animal models: preclinical evidence and promoting angiogenesis mechanism Zhang S , Tang DC , Zang WH , et al. , 2017 . Synergistic inhibitory effect of traditional Chinese medicine astragaloside IV and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma . Anticancer Res , 37 ( 2 ): 465 - 473 . https://doi.org/10.21873/anticanres.11338 https://doi.org/10.21873/anticanres.11338 Synergistic inhibitory effect of traditional Chinese medicine astragaloside IV and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma Zhao L , Zhu XD , Ni YQ , et al. , 2020 . Xiaoyaosan, a traditional Chinese medicine, inhibits the chronic restraint stress-induced liver metastasis of colon cancer in vivo . Pharm Biol , 58 ( 1 ): 1094 - 1100 . https://doi.org/10.1080/13880209.2020.1839513 https://doi.org/10.1080/13880209.2020.1839513 Xiaoyaosan, a traditional Chinese medicine, inhibits the chronic restraint stress-induced liver metastasis of colon cancer in vivo Zhao ZM , Liu HL , Sun X , et al. , 2017 . Levistilide A inhibits angiogenesis in liver fibrosis via vascular endothelial growth factor signaling pathway . Exp Biol Med , 242 ( 9 ): 974 - 985 . https://doi.org/10.1177/1535370217701005 https://doi.org/10.1177/1535370217701005 Levistilide A inhibits angiogenesis in liver fibrosis via vascular endothelial growth factor signaling pathway Zheng WL , Wang J , Wu JY , et al. , 2021 . Exploration of the modulatory property mechanism of ELeng Capsule in the treatment of endometriosis using transcriptomics combined with systems network pharmacology . Front Pharmacol , 12 : 674874 . https://doi.org/10.3389/fphar.2021.674874 https://doi.org/10.3389/fphar.2021.674874 Exploration of the modulatory property mechanism of ELeng Capsule in the treatment of endometriosis using transcriptomics combined with systems network pharmacology Zheng WW , Qian C , Xu FM , et al. , 2021 . Fuxin Granules ameliorate diabetic nephropathy in db/db mice through TGF-‍β1/Smad and VEGF/VEGFR2 signaling pathways . Biomed Pharmacother , 141 : 111806 . https://doi.org/10.1016/j.biopha.2021.111806 https://doi.org/10.1016/j.biopha.2021.111806 Fuxin Granules ameliorate diabetic nephropathy in db/db mice through TGF-‍β1/Smad and VEGF/VEGFR2 signaling pathways Zheng XW , Shan CS , Xu QQ , et al. , 2018 . Buyang Huanwu decoction targets SIRT1/VEGF pathway to promote angiogenesis after cerebral ischemia/reperfusion injury . Front Neurosci , 12 : 911 . https://doi.org/10.3389/fnins.2018.00911 https://doi.org/10.3389/fnins.2018.00911 Buyang Huanwu decoction targets SIRT1/VEGF pathway to promote angiogenesis after cerebral ischemia/reperfusion injury Zhou B , Yan ZP , Liu R , et al. , 2016 . Prospective study of transcatheter arterial chemoembolization (TACE) with ginsenoside Rg3 versus TACE alone for the treatment of patients with advanced hepatocellular carcinoma . Radiology , 280 ( 2 ): 630 - 639 . https://doi.org/10.1148/radiol.2016150719 https://doi.org/10.1148/radiol.2016150719 Prospective study of transcatheter arterial chemoembolization (TACE) with ginsenoside Rg3 versus TACE alone for the treatment of patients with advanced hepatocellular carcinoma Zhou H , Zhang Q , Yang BR , et al. , 2019a . Effect of Xiaoliu Decoction on proliferation and apoptosis of endometrial cells in patients with endometriosis . Mod Chin Clin Med , 26 ( 2 ): 52 - 55 (in Chinese) . https://doi.org/10.3969/j.issn.2095-6606.2019.02.011 https://doi.org/10.3969/j.issn.2095-6606.2019.02.011 Effect of Xiaoliu Decoction on proliferation and apoptosis of endometrial cells in patients with endometriosis Zhou H , Zhang Q , Qi C , 2019b . Impact of a Chinese medicinal formula, Xiao Liu Fang, on the “3A” ability of endometrial stromal cells in patients with endometriosis . Mol Ther-Oncolytics , 12 : 1 - 8 . https://doi.org/10.1016/j.omto.2018.11.001 https://doi.org/10.1016/j.omto.2018.11.001 Impact of a Chinese medicinal formula, Xiao Liu Fang, on the “3A” ability of endometrial stromal cells in patients with endometriosis Zhou SS , Ai ZZ , Li WN , et al. , 2020 . Deciphering the pharmacological mechanisms of Taohe-Chengqi decoction extract against renal fibrosis through integrating network pharmacology and experimental validation in vitro and in vivo . Front Pharmacol , 11 : 425 . https://doi.org/10.3389/fphar.2020.00425 https://doi.org/10.3389/fphar.2020.00425 Deciphering the pharmacological mechanisms of Taohe-Chengqi decoction extract against renal fibrosis through integrating network pharmacology and experimental validation in vitro and in vivo Zhou Y , Zhu XP , Cui HM , et al. , 2021 . The role of the VEGF family in coronary heart disease . Front Cardiovasc Med , 8 : 738325 . https://doi.org/10.3389/fcvm.2021.738325 https://doi.org/10.3389/fcvm.2021.738325 The role of the VEGF family in coronary heart disease Zhu HH , Wang S , Shan C , et al. , 2021 . Mechanism of protective effect of xuan-bai-cheng-qi decoction on LPS-induced acute lung injury based on an integrated network pharmacology and RNA-sequencing approach . Respir Res , 22 : 188 . https://doi.org/10.1186/s12931-021-01781-1 https://doi.org/10.1186/s12931-021-01781-1 Mechanism of protective effect of xuan-bai-cheng-qi decoction on LPS-induced acute lung injury based on an integrated network pharmacology and RNA-sequencing approach Yijia MAO drafted the manuscript. Huayi LIU put forward the idea and revised the manuscript. Lingkai MENG, Yuting LU, Kuo YANG, and Guangze OUYANG supervised the study. Yanran BAN and Shuang CHEN edited the tables, figure, and formats. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This work was supported by the Tianjin Sci-Tech Project (No. 16YFZCSY01070), China. 10.1631/jzus.B2101055 1673-1581（2022）05-0353-12 This work was supported by the Tianjin Sci-Tech Project (No. 16YFZCSY01070), China. 2021-12-13 2022-02-14 2022-05-15 2022-12-27 2022-04-11 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Yijia MAO, Lingkai MENG, Huayi LIU, Yuting LU, Kuo YANG, Guangze OUYANG, Yanran BAN, and Shuang CHEN declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 5 23