Yin and Yang of ginsenosides: Molecular mechanisms of bidirectional regulation of angiogenesis

P. ginseng is an ancient herbal medicine and ginsenosides are one of the major secondary metabolites in P. ginseng with a wide range of pharmacological effects, including anti-inflammatory, antioxidant, anti-cancer and angiogenic modulating activities [ 54 ]. Ginsenosides are a class of steroid compounds, each featuring a basic structure comprising a sterane nucleus formed by 30 carbon atoms arranged into four rings, linked to a sugar moiety. Based on the aglycone structure, ginsenosides can be classified into types such as dammarane-type and oleanane-type [ 55 ]. Based on the functional groups at the C6 position of ginsenosides, representative ginsenosides were divided into two major groups: protopanaxadiol groups (PPD) with one hydrogen atom on C3, including Rb2, Rg3, Rd, Rb1, Rh2, etc., and protopanaxatriol groups (PPT) with one C6 sugar side chain on C3, including Re, Rg1, F1, etc. It is noteworthy that ginsenosides derived from PPD and PPT exhibit distinct biological activities, such as angiogenesis [ 9 ]( as shown in Table 1 ).Consistent with the Yin-Yang principle, PPT-type ginsenosides (Yang) generally promote angiogenesis, whereas PPD-type ginsenosides (Yin) generally inhibit it, reflecting the opposing yet complementary forces that maintain vascular homeostasis. Table 1 Summary of ginsenoside structures and their angiogenic properties. Table 1 Group Representative ginsenosides No. R1 R2 R3 Angiogenic Property Key signaling pathways PPD Rb2 4 Glc-Glc H Glc-Ara(p) Anti- MMP-2/9, VEGF inhibition Rg3 2 Glc-Glc H H Anti- TGF-β/Smad, ERK, PI3K/Akt/mTOR, VEGFR2 Rd 3 Glc-Glc H Glc-Ara(f) Anti- VEGFR2, Akt/mTOR/P70S6K, ROCC/ERCC Rb1 4 Glc-Glc H Glc-Glc Pro-/Anti- STAT6/PPARγ (pro); VSMC inhibition (anti) Rh2 1 Glc H H Pro-/Anti- VEGFR2/Gab1/BP1, PI3K/Akt (anti); ERK, VEGFA/VEGFR2 (pro) PPT Re 3 H O-Glc-Rha Glc Pro-/Anti- HIF-1α/VEGF (anti); eNOS/NO/cGMP (pro); MAPK Rg1 2 H O-Glc Glc Pro- PI3K/Akt/eNOS, HIF-1α/VEGF, JAK2/STAT3, miRNAs F1 1 H H Glc Pro- IGF-1/IGF1R, ZP3 Summary of ginsenoside structures and their angiogenic properties. The pro- and anti-angiogenic effects of ginsenosides are essentially determined by their chemical structures. PPT-type ginsenosides (e.g., Rg1, F1) have a hydroxyl group at the C6 position, which gives them an inherent pro-angiogenic tendency. In contrast, PPD-type ginsenosides (e.g., Rb2, Rg3, Rd) lack the C6 hydroxyl group and tend to exert anti-angiogenic effects. Fewer sugar chains result in better cellular absorption and stronger biological activity, and the stereoconfiguration at the C20 position also modulates activity intensity (e.g., 20(S)-Rg3 exerts a more potent anti-angiogenic effect). Ginsenosides with bidirectional angiogenic activity (e.g., Rh2, Rb1, Re) can switch their effects in response to the body's microenvironment due to their flexible aglycone skeleton and sugar chain structures. PPT-type ginsenosides are usually pro-angiogenic, whereas PPD-type ginsenosides are often anti-angiogenic. For example, PPT-type ginsenoside Rg1 has been shown to promote vascular growth by inducing hypoxia-independent VEGF expression. In contrast, PPD-type ginsenoside Rg3 selectively inhibits VEGF expression [ 56 ] and blocks VEGF and BFGF-induced endothelial cell sprouting. Thus, the anti-angiogenic ginsenosides of the PPD family are considered as agents for the treatment of cancer, while the pro-angiogenic ginsenosides of the PPT family are considered as agents for the treatment of hypoxic-ischemic diseases. Similarly, different ginsenosides have different mechanisms of action in the regulation of angiogenesis. The anti-angiogenic ginsenoside compounds primarily include Ginsenoside Rb2, Ginsenoside Rg3, and Ginsenoside Rd. Their mechanisms of action and associated signaling pathways are illustrated in Fig. 3 . Fig. 3 Mechanism of action of ginsenoside compounds against angiogenesis. Ginsenoside Rb2 inhibits angiogenesis by suppressing MMP-associated proteins and regulating the expression of apoptotic proteins Bcl-2 and Bax. Ginsenoside Rg3 inhibits angiogenesis by suppressing the activation of the TGF-β pathway, ERK signaling pathway, and PI3K/Akt signaling pathway, while also regulating EMT progression through MMP expression inhibition. Furthermore, Ginsenoside Rd inhibits angiogenesis by suppressing the VEGF signaling pathway and MAPK signaling pathway. Mechanism of action of ginsenoside compounds against angiogenesis. Ginsenoside Rb2 inhibits angiogenesis by suppressing MMP-associated proteins and regulating the expression of apoptotic proteins Bcl-2 and Bax. Ginsenoside Rg3 inhibits angiogenesis by suppressing the activation of the TGF-β pathway, ERK signaling pathway, and PI3K/Akt signaling pathway, while also regulating EMT progression through MMP expression inhibition. Furthermore, Ginsenoside Rd inhibits angiogenesis by suppressing the VEGF signaling pathway and MAPK signaling pathway. As the main active components in P. ginseng , ginsenoside Rb2 inhibit angiogenesis. Intravenous or oral administration of Rb2 significantly inhibits the migration and invasion of melanoma cells. In addition, Sato et al. showed that Rb2 inhibits tumor angiogenesis by suppressing endothelial cell invasion through reconstituted basement membrane [ 57 ]. Mechanistically, Rb2 suppresses endothelial cell invasion and tube formation by downregulating matrix metalloproteinase-2 (MMP-2) and MMP-9 expression, thereby disrupting basement membrane integrity and reducing vascular permeability. This anti-angiogenic effect is further supported by its ability to inhibit VEGF-induced endothelial cell proliferation and migration. Ginsenoside Rg3 influences tumor angiogenesis through multi-target regulation of tumor cells. Currently, its biological effects in inhibiting tumor angiogenesis have been extensively validated in both in vivo and in vitro experiments [ 58 ]. The reduction of VEGF mRNA expression levels and p-ERK1/2 protein expression levels inhibited keloid fibroblast proliferation [ 59 ]. Rg3 inhibits VEGF protein expression in human hepatocytes (HepG2) and esophageal carcinoma (ECA-109) and decreases VEGF-A expression in mesenchymal and papillary thyroid cancer cell lines [ 60 ]. Chen et al. published in Cell Death and Disease showed that 20(S)-Rg3 suppresses angiogenesis through inhibition of NKILA-mediated VEGFA secretion in gliomas [ 61 ]. Ginsenoside Rg3 can downregulate the expression of VEGF and TNF-α in the retina and is involved in the development and progression of diabetic retinopathy. Ginsenoside Rg3 downregulates the expression of retinal VEGF and TNF-α and is involved in the development of diabetic retinopathy [ 62 ].Research has found that ginsenoside Rg3 can inhibit angiogenesis by downregulating the expression of VE-cadherin, EphA2, MMP-9, and MMP-2, thereby effectively suppressing the formation of vascular mimicry (VM) by pancreatic cancer cells both in vivo and in vitro [ 63 ]. Rg3 can also regulate angiogenesis by participating in different signaling pathways. Rg3 inhibits fibroblast proliferation and migration via the TGF-β/Smad and ERK signalling pathways. Another study also found that ginsenoside Rg3 exerts anti-angiogenic effects by inhibiting the TGF-β/SMAD and ERK signaling pathways, thereby reducing the expression levels of VEGF, VEGFR, and PDGF, while simultaneously suppressing the activation of the PI3K/Akt and ERK1/2 pathways [ 64 ]. Rg3 at 300 ng/ml reduces VEGF-dependent Akt/eNOS signaling in EPCs [ 65 ], which in turn regulates the angiogenic process. A rat model of endometriosis receiving 10 mg/kg/day of Rg3 for 3 weeks resulted in blockage of the VEGFR2-mediated PI3K/Akt/mTOR signaling pathway, thereby inhibiting angiogenesis in rats with endometriosis [ 66 ]. Ginsenoside Rg3 reduces VEGF expression in acute leukemia patients by inactivating PI3K/Akt and ERK1/2 pathways [ 67 ]. Further analysis of the expression of angiogenesis-related genes in Rg3-treated CRC cells by applying real-time PCR revealed that 22 pro-angiogenic genes were significantly downregulated [ 68 ]. Conversely, Choi et al. In Frontiers in Pharmacology demonstrated that the Rb2/Rg3 combination promotes angiogenesis via PI3K/Akt and MAPK pathways through upregulation of CXCL8 and FGF16 expression [ 69 ]. This apparent contradiction—where Rg3 alone exerts anti-angiogenic effects but the Rb2/Rg3 combination promotes angiogenesis—highlights the complexity of ginsenoside interactions. It suggests that combination effects cannot be simply predicted from individual compound activities, as synergistic modulation of multiple signaling pathways (e.g., PI3K/Akt and MAPK) may override the anti-angiogenic effect of Rg3 alone. From a therapeutic perspective, this underscores the importance of considering both the combination context and the specific pathological microenvironment when designing ginsenoside-based therapies. Ginsenoside Rd is a P. ginseng protopanaxadiol-type ginsenoside that is an active component of various oriental herbs. According to Zhang et al., Rd greatly inhibited the activation of VEGFR2 induced by VEGF in HUVECs. Moreover, under both normoxic and hypoxic conditions, Rd inhibited the activation of Akt/mTOR signaling pathway that is also induced by VEGF. Also, the use of Rd in a mouse model of breast cancer reduced the solid tumors and tumor angiogenesis volumes and weights. Rd was shown to inhibit breast cancer by Akt/mTOR/P70S6 kinase signaling [ 70 ]. Aside from directly affecting tumor cells and signaling in endothelial cells, ginsenoside Rd acts on VSMCs, which are part of the tumor vasculature. These mostly take part in tumor type-associated abnormal vascular remodeling. Ginsenoside Rd significantly reduces Ca 2+ influx into the cytoplasm of vascular smooth muscle cells (VSMCs) by inhibiting receptor-operated calcium channels (ROCCs) and endoplasmic reticulum-operated calcium channels (ERCCs), thereby regulating cellular function. This, in turn, attenuates the vasoconstrictor response as well as suppresses the proliferation of ET-1-induced cerebral artery smooth muscle cells (SAMCs). Finally, ginsenoside Rd also ameliorates pathological vascular remodeling [ 71 ]. Given that VSMCs contribute to abnormal vascular remodeling in the tumor microenvironment—such as promoting vessel leakiness and providing structural support for tumor angiogenesis—Rd-mediated inhibition of VSMC function may further suppress tumor angiogenesis by stabilizing vascular structure and reducing pathological neovascularization. All anti-angiogenic ginsenosides discussed in this section belong to the PPD type without a hydroxyl group at the C6 position. Their anti-angiogenic activity is positively correlated with the degree of deglycosylation (Rd > Rg3 > Rb2). Owing to its stereoconfigurational advantage, 20(S)-Rg3 exerts the strongest inhibitory effect on angiogenesis-related signaling pathways. From a Yin-Yang perspective, ginsenosides with bidirectional activity exemplify the dynamic interplay and mutual transformation of opposing forces. Under different pathological contexts, the same compound can exert either pro-angiogenic (Yang) or anti-angiogenic (Yin) effects, embodying the philosophical principle that extremes can transform into their opposites. Ginsenosides including Rb1, Rh2 and Re exhibit context-dependent bidirectional angiogenic regulatory effects. The switch between pro- and anti-angiogenic activities is determined by three key factors:Dosage, Target cell type (tumor endothelial cells vs. normal endothelial cells), Pathological microenvironment (ischemic, inflammatory, or tumor microenvironment). These factors collectively regulate the activation of downstream signaling pathways, leading to opposite angiogenic outcomes. The active components in ginsenoside compounds that exhibit both anti-angiogenic and pro-angiogenic effects primarily include Ginsenoside Rb1, Ginsenoside Rh2, and Ginsenoside Re. Their related mechanisms of action are illustrated in Fig. 4 . Notably, Rb1 is a PPD-type ginsenoside but exhibits dual angiogenic activity. This apparent exception does not contradict the PPD/PPT framework; rather, it reflects the structural flexibility of its aglycone skeleton and sugar chain, which enable context-dependent interactions with distinct signaling pathways. Similarly, Rh2 (PPD-type) and Re (PPT-type) also demonstrate bidirectional activity, indicating that structural features beyond the C6 hydroxyl group—such as sugar chain number and stereoconfiguration—contribute to functional diversity. Fig. 4 The relevant mechanisms of action among ginsenoside active components that exhibit both anti-angiogenic and pro-angiogenic effects. Ginsenoside Rb1 induces M2 polarization in macrophages by activating the STAT6 pathway, thereby promoting angiogenesis. Simultaneously, it modulates PEDF expression via the ERβ receptor pathway to inhibit angiogenesis. Ginsenoside Rh2 suppresses angiogenesis through VEGF signaling and the PI3K/Akt pathway. Additionally, it regulates cell cycle protein expression and modulates apoptosis to inhibit angiogenesis. In contrast, both Ginsenoside Rh2 and Ginsenoside Re promote angiogenesis by inducing vascular endothelial cell proliferation through the ERK signaling pathway. Additionally, Ginsenoside Re inhibits angiogenesis via the eNOS/NO signaling pathway and the VEGF and MAPK signaling pathways. The relevant mechanisms of action among ginsenoside active components that exhibit both anti-angiogenic and pro-angiogenic effects. Ginsenoside Rb1 induces M2 polarization in macrophages by activating the STAT6 pathway, thereby promoting angiogenesis. Simultaneously, it modulates PEDF expression via the ERβ receptor pathway to inhibit angiogenesis. Ginsenoside Rh2 suppresses angiogenesis through VEGF signaling and the PI3K/Akt pathway. Additionally, it regulates cell cycle protein expression and modulates apoptosis to inhibit angiogenesis. In contrast, both Ginsenoside Rh2 and Ginsenoside Re promote angiogenesis by inducing vascular endothelial cell proliferation through the ERK signaling pathway. Additionally, Ginsenoside Re inhibits angiogenesis via the eNOS/NO signaling pathway and the VEGF and MAPK signaling pathways. Rb1 is an important traditional Chinese medicine that is a major bioactive component of P. ginseng . It reduces heart disease by blocking inflammation (swelling) in the heart (myocardium) and its damage and growth [ 55 , 72 ]. Histological test shows that ginsenoside Rb1 can lead to M2 macrophage polarization through the STAT6/PPARγ pathway and upregulates VEGF-A secretion improving angiogenesis [ 73 ]. The bidirectional effect of Rb1 is mainly dependent on the pathological microenvironment and target cell types: in the ischemic cardiac microenvironment (normal myocardial endothelial cell context), Rb1 polarizes M2 macrophages via the STAT6/PPARγ pathway and upregulates VEGF-A secretion to promote angiogenesis and repair damaged myocardial blood vessels; while in the inflammatory microenvironment of vascular remodeling, Rb1 inhibits the activation of pro-inflammatory factors and abnormal proliferation of vascular smooth muscle cells, thereby exerting an anti-angiogenic effect to alleviate pathological neovascularization, and shows no obvious dose dependence within the conventional therapeutic window. Ginsenoside Rh2 has a very important and valuable biological activity. Ginsenoside Rh2 is one of the bioactive components of P. ginseng extracts. Ginsenoside possesses potent angiogenic modulating activity. Researchers discovered that Rh2 inhibited VEGF-induced angiogenic effects by blockade of the VEGFR2/Growth factor receptor-binding protein 2 (Gab1) binding protein 1 (BP1) signaling pathway in vitro. Moreover, it also blocked alkali burn angiogenesis and inflammatory response in the mouse cornea. Multiple studies have demonstrated that angiogenesis, as a key pathophysiological process, contributes to the pathogenesis of psoriasis by mediating endothelial cell activation and the secretion of inflammatory cytokines. Research has found that activation of pathways such as vascular endothelial growth factor and hypoxia-inducible factor-1α promotes endothelial cell proliferation and migration, increases vascular density, thereby exacerbating inflammatory infiltration and epidermal hyperplasia, and accelerating the progression of psoriasis. Treatment with different doses of Rh2 revealed that Rh2 significantly reduced the vascular density of mice. We found that Rh2 exerted this modulatory effect based upon the inhibition of VEGF-A expression levels in PN implants by Rh2 [ 74 ]. The ginsenoside Rh-2 suppresses the proliferation of endothelial cells to inhibit tumor angiogenesis. Also, Rh2 can down regulate cell cycle protein D1 which helps in a Bxpc-3 proliferation of pancreatic cancer cells. Moreover, it can control upregulation of MMP-2 and MMP-9 in interference of tumor angiogenesis [ 75 ]. Interestingly, the dose-dependent treatment of ginsenoside Rh2 and its octyl ester derivative (Rh2-O) was found to inhibit wound healing and colony formation of HUVECs. It also inhibited the phosphorylation of PI3K, Akt, mTOR, and STAT3, which triggered the blocking of the PI3K/Akt and PI3K/STAT signalling pathways. Thus, the treatment was found to effectively suppress VEGFA expression and secretion, inhibiting the tumour-associated angiogenesis in liver cancer [ 76 ]. By contrast. It has been reported that co-treatment with ginsenoside Rh2 and chrysophanol promotes angiogenesis in the recovery phase after intracerebral hemorrhage via activation of VEGFA/VEGFR2 signaling and up-regulation of downstream effectors SRC, Akt1 and MAPK1 [ 77 ]. It has been reported that ginsenoside Rh2 (200 ng/mL) treatment promotes angiogenesis in the hearts of post-myocardial infarction rats through ERK signaling pathway activation. This is evident from ERK phosphorylation enhancement along with HUVECs MIgration in scratch assay and capillary-like tube formation increase in vitro. Further, U0126 treatment nullifies the ginsenoside treatment effect [ 78 ]. Rh2 is the most typical ginsenoside with context-dependent bidirectional angiogenic activity, and its effect switch is determined by all three factors: dosage, cell type, and pathological microenvironment. Cell type specificity: Rh2 blocks the VEGFR2/Gab1/BP1 pathway to inhibit VEGF-induced angiogenesis in tumor endothelial cells, while it activates the ERK pathway to promote proliferation and tube formation of normal cardiac endothelial cells in myocardial ischemic tissue. Dosage dependence: Low-to-moderate doses of Rh2 (≤200 ng/mL) promote angiogenesis in ischemic models (e.g., post-intracerebral hemorrhage and myocardial infarction), whereas high doses of Rh2 and its derivative Rh2-O significantly inhibit the PI3K/Akt pathway in HUVECs and suppress tumor-associated angiogenesis. Pathological microenvironment: In the pro-inflammatory and hyperproliferative microenvironment of psoriasis and tumor tissues, Rh2 downregulates VEGF-A and MMP-2/9 expression to exert anti-angiogenic effects; in the hypoxic-ischemic microenvironment of brain and heart tissue, it upregulates VEGFA/VEGFR2 signaling to promote angiogenesis and tissue repair. In addition, synergistic use of Rh2 with other compounds (e.g., chrysophanol) can further enhance its pro-angiogenic effect in ischemic microenvironments, which also reflects the microenvironment-dependent characteristics of its bidirectional activity. Ginsenoside Re is the main ginsenoside and important component of P. ginseng leaves, berries and roots [ 79 ], which exhibits a variety of pharmacological activities in vivo and in vitro. Research found that Re improved high glucose (HG) induced retinal angiogenesis through the HIF-1α/VEGF signaling pathway, regulating HIF-1α expression, inhibited VEGF activity, and exerted a protective effect on retinal microendothelial cells [ 80 ]. Re also inhibited vascular neointimal proliferation and improved atherosclerosis through the eNOS/NO/cGMP pathway [ 81 ]. Shi et al. confirmed that Re could prevent diabetes by decreasing the expression levels of VEGF and IL-6 and increasing the expression levels of NO diabetes, and this effect may be achieved through MAPK signaling pathway [ 82 ]. The bidirectional angiogenic regulation of Re is mainly dominated by the pathological microenvironment and the functional state of target endothelial cells: in the high-glucose microenvironment of retinal microvascular endothelial cells (diabetic retinopathy), Re downregulates HIF-1α/VEGF signaling to inhibit abnormal retinal neovascularization and reduce vascular leakage; in the atherosclerotic microenvironment, it activates the eNOS/NO/cGMP pathway to suppress pathological vascular neointimal hyperplasia; while in the mild inflammatory microenvironment of vascular injury repair, Re modulates the MAPK pathway to balance pro- and anti-angiogenic factors and promotes normal collateral vessel formation. Re shows no obvious dose-dependent bidirectional effect within conventional pharmacological concentrations, and its activity switch is closely linked to the expression levels of key signaling molecules (e.g., VEGF, IL-6) in the pathological microenvironment. The bidirectional angiogenic activity of these ginsenosides arises from their structural flexibility. Rh2 and Rb1 are PPD-type ginsenosides with short sugar chains, whereas Re is a PPT-type ginsenoside with a longer sugar chain. Their flexible aglycone skeletons and variable sugar chains enable differential binding to signaling pathways, thereby switching between pro- and anti-angiogenic effects according to the in vivo pathological microenvironment (ischemia, tumorigenesis, or inflammation). The compounds in ginsenosides that promote angiogenesis primarily include Ginsenoside Rg1 and Ginsenoside F1. Their mechanisms of action and signaling pathways for promoting angiogenesis are illustrated in Fig. 5 . Fig. 5 The mechanism of action of Ginsenosides in promoting angiogenesis. Ginsenoside Rg1 promotes angiogenesis by regulating VEGF expression through modulating miR-23a and miR-489 expression. Simultaneously, it induces EMT via miR-15b. Furthermore, ginsenoside Rg1 activates the PI3K/Akt/mTOR signaling pathway to exert its pro-angiogenic effects. Additionally, CD31 serves as a key target for ginsenoside Rg1-induced angiogenesis. Furthermore, ginsenoside F1 promotes angiogenesis through the IGF-1/IGF-1R pathway. Simultaneously, it activates the downstream NF-κB signaling pathway by enhancing VEGF expression, thereby exerting its pro-angiogenic effects. The mechanism of action of Ginsenosides in promoting angiogenesis. Ginsenoside Rg1 promotes angiogenesis by regulating VEGF expression through modulating miR-23a and miR-489 expression. Simultaneously, it induces EMT via miR-15b. Furthermore, ginsenoside Rg1 activates the PI3K/Akt/mTOR signaling pathway to exert its pro-angiogenic effects. Additionally, CD31 serves as a key target for ginsenoside Rg1-induced angiogenesis. Furthermore, ginsenoside F1 promotes angiogenesis through the IGF-1/IGF-1R pathway. Simultaneously, it activates the downstream NF-κB signaling pathway by enhancing VEGF expression, thereby exerting its pro-angiogenic effects. Ginsenoside Rg1 is the most common active component of P. ginseng and various tests have shown its strong pro-angiogenic effect. MicroRNA regulates the different expression of genes by the target mRNA cleavage or translational repression and plays an important role in the pathological process of numerous diseases [ 83 ]. Multiple studies have consistently demonstrated that Rg1 promotes angiogenesis through miRNA-mediated regulation. Specifically, Rg1 has been shown to promote endothelial cell proliferation, migration, and tube formation by downregulating miR-15b and miR-23a, thereby increasing VEGFR-2 and MET expression [ 84 , 85 ]. Additionally, Rg1 enhances eNOS phosphorylation and iNOS activity via the miR-489-3p/Sirt1 axis, contributing to VEGF expression and angiogenesis [ 86 ]. Rg1 is also considered to be a possible phytosteroid that serves as a functional ligand for steroid receptors, like GR. In HUVECs, it activates the GR and FGFR-1 synergistically for non-genomic signaling through the PI3K/Akt/eNOS pathway and promotes angiogenesis [ 87 ]. Treatment of HUVEC with Rg1 increases HIF-1α expression and promotes angiogenesis through the PI3K/Akt/P70S6K pathway, as p70S6K can activate mRNA encoding HIF-1α [ 88 ]. In the diabetic (DM) population, neovascularization and collateral vessel formation are usually impaired due to defective VEGF signaling and eNOS dysfunction. In a diabetic peripheral artery disease (PAD) model, the treatment with Rg1 significantly promoted eNOS phosphorylation and induced VEGF protein expression in vivo and inhibited apoptosis in ischemic tissue and improved the reperfusion of ischemic limbs [ 89 ]. Hypoxic-ischemic (HI) brain damage can result in neurological dysfunction in newborns. In addition, brain repair is associated with improved angiogenesis. Rg1 enhances blood vessel formation in living organisms after HI by using HIF-1α and VEGF signals [ 90 ]. Ginsenoside Rg1 also activates the PI3K/Akt/mTOR signaling pathway after stroke, which induces upregulation of VEGF and significantly promotes cerebral angiogenesis, as indicated by a dMCAO mouse model [ 91 ]. Rg1 can alleviate pathological vascular remodeling through the inhibition of EndMT and Inflammation under hypoxic conditions. This happens with the improved expression of CCN1 and further inhibition of the NF-κB/TGF-β signal pathway [ 92 ]. In a model of tibial dyschondroplasia in broilers induced by thiram, Rg1 ameliorates impaired angiogenesis by upregulating the HIF-1α/VEGFA/VEGFR2 signaling pathway [ 93 ]. In addition, Rg1 significantly promotes angiogenesis after spinal cord injury (SCI) by activating astrocytes and upregulating key angiogenic factors (VEGF, Ang-2 and Laminin) via the JAK2/STAT3 signaling pathway. In vivo experiments have also confirmed that Rg1 promotes the proliferation, migration, and differentiation of endothelial cells [ 94 ]. Ginsenoside Rg1 and ginsenoside Re have been widely used as pro-angiogenic agents in experimental studies, while ginsenoside F1 also possesses pro-angiogenic activity. Research has demonstrated that F1 can increase blood flow in ischaemic regions by enhancing microvascular density in the brain through activation of the IGF-1/IGF1R signalling pathway in endothelial cells, thereby mitigating the severity of cerebral ischemia. This confirms that F1 promotes neuro-recovery in ischaemic stroke by inducing angiogenesis [ 95 ]. Ginsenoside F1 effectively induces migration, proliferation, and tubulogenesis in human umbilical vein endothelial cells (HUVECs) and human retinal microvascular endothelial cells (HRMECs). Remarkably, its proangiogenic mechanism differs from VEGF-mediated signaling pathways, exerting effects by regulating unique gene expression profiles such as the zona pellucida sperm-binding protein 3 (ZP3) gene. Furthermore, while F1 exhibits pro-angiogenic activity, it does not induce vascular leakage like VEGF. Instead, it significantly inhibits VEGF-induced vascular leakage. This dual characteristic positions it as a potential therapeutic agent for vascular normalization [ 96 ]. All pro-angiogenic ginsenosides in this section are PPT-type with a hydroxyl group at the C6 position, which is the key structural feature for activating pro-angiogenic signaling pathways. F1 is a deglycosylated metabolite of Rg1, with fewer sugar chains and higher cellular bioavailability, consequently exerting a more direct and stronger pro-angiogenic effect than its parent compound Rg1.

Therapeutic strategies that target angiogenesis provide a viable pathway to treat a variety of diseases [ 51 ]. For example, by “normalizing” abnormal blood vessels in tumors, thereby improving the efficacy of chemotherapy and immunotherapy. Many drugs targeting angiogenesis have been licensed by the US Food and Drug Administration (FDA). However, current therapeutic agents that modulate angiogenesis are flawed. For example, treatment with the VEGF receptor inhibitor bevacizumab increases the risk of cardiovascular adverse effects in oncology patients, including hypertension, arrhythmia and atherosclerosis [ 52 ]. In the search for rational therapeutic approaches to deal with complex pathological conditions, attention has turned to natural products, which often consist of multiple active ingredients capable of exerting a regulatory angiogenic effect through multiple cellular and molecular targets [ 53 ].

Angiogenesis regulation involves the actions of both agonists and inhibitors [ 11 ], including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietins (Ang), transforming growth factor β (TGF-β), tumour necrosis factor-α (TNF-α), protein pigment epithelium-derived factor (PEDF) and matrix metalloproteinases (MMPs) [ [12] , [13] , [14] ]. Nonetheless, the regulatory factors for angiogenesis are unknown, while ample evidence has been presented that inflammation and oxidative stress are important in angiogenesis [ 15 , 16 ]. The molecular mechanisms affecting angiogenesis are shown in Fig. 2 . Fig. 2 Molecular mechanisms influencing angiogenesis. Common inflammatory cytokines IL-1 and TNF-α induce cellular inflammatory responses by activating downstream NF-κB, MAPK, and PI3K/Akt signaling pathways. Concurrently, NAD + activates mitochondrial ROS expression, inducing activation of the PI3K/Akt signaling pathway and HIF-1 pathway, thereby triggering oxidative stress. This regulates intracellular expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFR1, VEGFR2), ultimately influencing angiogenesis. Molecular mechanisms influencing angiogenesis. Common inflammatory cytokines IL-1 and TNF-α induce cellular inflammatory responses by activating downstream NF-κB, MAPK, and PI3K/Akt signaling pathways. Concurrently, NAD + activates mitochondrial ROS expression, inducing activation of the PI3K/Akt signaling pathway and HIF-1 pathway, thereby triggering oxidative stress. This regulates intracellular expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFR1, VEGFR2), ultimately influencing angiogenesis. The inflammatory response is a complex physiological process involving the coordinated action of different types of cytokines that control tissue damage in a coordinated manner from pathogenic, traumatic or toxic injury [ 17 ]. Angiogenesis, as a multistep cascade reaction, sequentially involves the degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs), followed by the proliferation and migration of endothelial cells, ultimately culminating in the formation of capillaries [ 18 ]. There is a strong interaction between inflammatory processes and pathological angiogenesis according to a large body of evidence. The release of various pro-inflammatory cytokines and chemokines during the inflammatory response can effectively activate endothelial cells. [ 19 ]. The immune cells release inflammatory mediators which target endothelial cells and release the angiogenic factors which set up angiogenesis [ 20 ]. Activated endothelial nitric oxide synthase (eNOS) serves both as a key inflammatory mediator within the body and as one of the pivotal cytokines in angiogenesis [ 21 ]. eNOS plays a crucial role in regulating vascular permeability by releasing nitric oxide. Research has demonstrated that activation of the PI3K/Akt signalling pathway promotes endothelial cell angiogenesis by inducing eNOS phosphorylation and VEGF secretion. [ 22 ]. Another experiment also confirmed that VEGF stimulation activates the Akt signalling pathway, which plays a crucial role in the process of angiogenesis [ 23 ]. Additionally, studies indicate that Akt signaling can also directly induce eNOS secretion, thereby increasing vascular permeability [ 24 ]. The MAPK signaling pathway is a highly conserved intracellular signaling pathway in eukaryotes, primarily comprising three subpathways: ERK, JNK, and p38 [ 25 ]. This pathway integrates and transmits multiple extracellular stimuli, participating in key biological processes such as cell proliferation, migration, differentiation, and apoptosis by regulating the expression of downstream target genes [ 26 ]. VEGF is the primary ligand for growth factor receptor binding 2 (VEGFR2) [ 27 ], and VEGFR2 is involved in the angiogenic process by interacting with VEGF, phosphorylating and activating the JNK signaling pathway and the p38 MAPK signaling pathway [ 13 ]. Inflammatory factors produced during inflammation, such as TNF-α, IL-1, and IL-6, can feedback to endothelial cells and regulate angiogenesis. Research has found that in human dental pulp cells (HDPCs), TNF-α promotes angiogenesis by activating the PI3K and MAPK signaling pathways and downstream NF-κB signaling through upregulating the VEGF-SIRT1 signaling axis, thereby enhancing the expression of MMP-2 and MMP-9 [ 28 ]. Another experiment also confirmed TNF-α induces VEGFA expression and promotes endothelial cell angiogenesis through activation of downstream NF-κB signaling [ 29 ]. TNF-α can induce endothelial cell death during inflammation through cystathione-dependent apoptosis or receptor-interacting protein (RIP1) kinase-dependent necrosis [ 30 ]. As a key pro-inflammatory cytokine, IL-1 activates downstream inflammatory signaling pathways to induce the formation of a local inflammatory microenvironment. This process subsequently upregulates the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), ultimately mediating endothelial cell proliferation and migration to promote angiogenesis [ 31 ]. In a mice model of prostate cancer, inhibiting the expression of the inflammatory cytokine IL-1α significantly suppresses the downstream NF-κB signaling pathway. This, in turn, modulates the polarization of tumor-associated macrophages and inhibits angiogenesis in vascular endothelial cells, thereby suppressing the development and progression of prostate cancer cells [ 32 ]. Moreover, IL-1 can activate the NF-κB pathway, promoting angiogenesis in melanoma cells and accelerating tumour progression [ 33 ]. Similarly, IL-1 and IL-1β can bind to their respective receptors through JNK and p38 MAPK signaling by inducing the expression of Ang-1, human angiopoietin receptor tyrosine kinase 2 (TIE-2) and VEGF [ 34 ]. Furthermore, the study revealed that IL-6 promotes hepatocellular carcinoma angiogenesis via the IL-6/STAT3/VEGFA signalling pathway [ 35 ]. Oxidative stress refers to an imbalanced state where the production rate of reactive oxygen species (ROS) within cells or organisms exceeds the scavenging capacity of the antioxidant system, leading to the accumulation of free radicals [ 36 ]. This imbalance can cause oxidative damage to biomolecules, thereby participating in the regulation of various physiological and pathological processes such as cell proliferation, apoptosis, and inflammatory responses [ 37 ]. ROS as key signaling molecules, can bidirectionally regulate angiogenesis when their levels are imbalanced. Moderate ROS activation can stimulate signaling pathways such as VEGF and MAPK, promoting endothelial cell proliferation and migration. Excessive ROS, however, induces oxidative stress, damages endothelial cells, and inhibits angiogenesis, making it a significant factor in the development and progression of ischemic diseases and tumors [ 38 ]. Evidence indicates that in the pathological progression of numerous refractory diseases, such as tumors, atherosclerosis, and diabetic microvascular complications, angiogenesis is influenced by oxidative stress [ 39 ]. Under oxidative stress conditions, ROS are primarily generated by mitochondria and serve as key regulatory factors in various pathological processes such as cell proliferation, differentiation, and angiogenesis [ 40 ]. Additionally, growth factors such as VEGF, FGF, and TGF-β released by tumor cells and macrophages activate receptors on the surface of endothelial cells, recruiting and activating NADPH oxidase (Nox) to generate ROS. This subsequently promotes endothelial cell proliferation and migration through signaling pathways including ERK, PI3-K/Akt, and Src [ 41 ]. ROS has been shown to promote metastasis and angiogenesis by stabilizing hypoxia-inducible factor (HIF) and activating single-carbon metabolism and the phosphoadenosine-activated protein kinase (AMPK) signaling network to enhance NADPH production [ 42 ]. Research has revealed that under hypoxic conditions, reactive oxygen species production markedly increases, promoting the formation of stable dimers between HIF-1α and HIF-1β. This subsequently drives the expression of hypoxia response elements, thereby facilitating angiogenesis within tumour tissues [ 43 ]. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit. Its activity is primarily regulated by the stability of HIF-1α [ 44 ]. HIF-1 is a heterodimer composed of HIF-1α and HIF-1β subunits [ 45 ]. HIF-1α is tightly regulated by changes in oxygen status, and at normal O 2 concentrations, prolyl hydroxylase (PHD) hydroxylates specific HIF-1α proline residues [ 46 ], and tumor suppressor proteins negatively regulate HIF-1α-mediated tumor angiogenesis and invasive metastasis by modulating the ubiquitin-mediated degradation, nuclear translocation, or transcriptional activity of HIF-1α [ 47 ]. Under various external stimulus conditions, multiple signalling pathways participate in regulating HIF-1α expression. Upon activation, HIF-1α participates in the regulation of a series of key angiogenesis genes, including VEGF, Ang and MMP-9, thereby regulating angiogenesis. HIF-1α/VEGFR-mediated activation of Akt/mTOR/P70S6K plays many roles in tumorigenesis [ 48 , 49 ]. HIF-1α also prevents active macrophage-induced angiogenesis by decreasing VEGF and MMP-9 expression, an effect that also affects the motility and invasion of HUVECs [ 50 ].

Pathological angiogenesis has an important causal relationship with the development of many diseases. Angiogenesis involves the formation of new blood vessels from existing vessels and is controlled by endogenous factors such as pro- and anti-angiogenesis [ 5 ]. However, once the balance is disturbed, the organism undergoes a series of pathological changes. Excessive angiogenesis plays an important role in the development of tumors, while insufficient angiogenesis can have effects on myocardial ischemia, diabetes, and stroke. Therefore, the development of drugs for angiogenesis has become a hot research topic in the current society. Since ancient times, P. ginseng has been used as an important premium Chinese medicinal herbs to treat various diseases, and ginsenosides are the main active ingredients of P. ginseng , which have a significant role in it. Increasing evidence suggested that ginsenosides play an active role in regulating angiogenesis, and that different types of ginsenosides produce two opposing mechanisms of action, pro-angiogenesis or anti-angiogenesis. The dual regulation of angiogenesis by ginsenosides is mainly achieved by up-regulating or down-regulating the expression levels of VEGF, HIF-1α, MMP and other cytokines through PI3K/Akt/mTOR, MAPK, JNK and NF-κB etc. This bidirectional regulation exemplifies the Yin-Yang principle of dynamic balance, where the same class of compounds can exert opposing effects depending on the structural context (PPD vs. PPT), the pathological microenvironment, and the cellular target. The essence of these differential regulatory effects is determined by the structural characteristics of ginsenosides: the aglycone skeleton (PPD/PPT) defines the basic tendency of pro- or anti-angiogenesis, the number of sugar chains and stereoconfiguration regulate the intensity and specificity of the effects, and the structural flexibility of ginsenosides with bidirectional activity is the core reason for their adaptation to different pathological microenvironments. In conclusion, ginsenosides represent a promising class of candidate compounds for angiogenesis-related diseases. However, significant translational barriers remain, including limited oral bioavailability, lack of well-controlled clinical trials, and the context-dependent nature of their effects. Future priorities should include pharmacokinetic optimization through novel formulations, well-designed clinical trials to validate efficacy and safety, and systematic investigation of combination therapies. Addressing these challenges will be essential to realize the therapeutic potential of ginsenosides in clinical practice.

The structural classification of ginsenosides into PPD and PPT types provides a mechanistic basis for their distinct angiogenic activities. PPT-type ginsenosides, with a hydroxyl group at the C6 position, consistently activate pro-angiogenic pathways such as PI3K/Akt and MAPK, while PPD-type ginsenosides, lacking this group, tend to suppress these pathways. This structure-activity relationship aligns with the Yin-Yang framework, where opposing effects arise from subtle structural variations. The bidirectional activity of ginsenosides such as Rh2, Rb1, and Re exemplifies the dynamic nature of this framework, demonstrating that context-dependent interactions enable a single molecule to exert opposing effects under different conditions. Despite promising preclinical evidence, several translational barriers remain. First, the oral bioavailability of ginsenosides is limited due to poor absorption and extensive gut microbiota metabolism, which varies substantially among individuals. Second, dose-dependent and context-dependent effects (e.g., Rh2 promotes angiogenesis at low doses but inhibits it at high doses) complicate therapeutic dosing. Third, the current evidence base is predominantly derived from in vitro and animal studies; few clinical trials have evaluated the angiogenic effects of ginsenosides in patients. Compared to FDA-approved anti-angiogenic agents (e.g., bevacizumab, sunitinib), ginsenosides offer multi-target regulation and context-dependent flexibility, but lack standardized dosing regimens and robust clinical efficacy data. Future research should prioritize: (1) pharmacokinetic optimization through formulation strategies; (2) well-designed clinical trials to validate efficacy; (3) investigation of combination therapies; and (4) exploration of gut microbiota–ginsenoside interactions for personalized approaches. As a narrative review, this article does not follow a systematic methodology. The selection of studies was based on relevance and may not be exhaustive, representing a limitation of this work.

Angiogenesis is the biological process by which new blood vessels are formed from existing blood vessels through the proliferation, migration, and tube formation of endothelial cells. It is useful in wound healing, tissue repair, etc. In addition, it plays a significant role in the development of many diseases, like cancer, diabetes, etc. The biology of angiogenesis is influenced by endogenous regulatory factors, cellular microenvironment, and exogenous stimuli provide signals for the growth of endothelial cells and vasculature. To develop successful therapies for either enhancing or inhibiting angiogenesis, it is important to understand how angiogenesis works. Clinical investigations have indicated that the development of tumors is intimately related to angiogenesis, whereas the overexpression of angiogenesis may enhance tumor progression and metastasis [ 1 ]. Likewise, experimental studies associated with vascular eye disease suggest a causal relationship between diabetic macular degeneration and ocular neovascularization that is abnormally increased [ 2 ]. Neovascularization occurs early on in rheumatoid arthritis (RA) and plays a pivotal role in the development of proliferative hyperplastic synovium [ 3 ]. A study found that local angiogenesis at the site of infarct in the ischaemic heart can heal ischemic heart disease [ 4 ]. At present, it is considered that anti-angiogenic therapy can be used as a new oncologic treatment modality and treatment to promote angiogenesis as a key strategy to improve the clinical management of ischemic diseases [ 5 ]. Many compounds isolated from herbs or natural products have been used to study the regulation of angiogenesis. Among them, Panax ginseng Meyer ( P. ginseng ) is a common tonic drug and enjoys the reputation of “king of herbs”. Ginsenosides, as the main active substances of P. ginseng , have attracted the attention of many researchers due to their multi-target, multi-pathway and low side effects [ 6 ]. Increasing evidence suggests that ginsenosides possess multiple pharmacological activities. For example, Xu et al. found that ginsenoside Rh2 treated ulcerative colitis by inhibiting secretion levels of various inflammatory factors [ 7 ]. Gao et al. showed that ginsenoside Rg2 alleviated anxiety via the hypothalamic-pituitary-adrenal (HPA) axis in rats with PTSD [ 8 ]. At the same time, research has also found that ginsenosides can exert anti-tumor, ameliorate myocardial ischemia and improve atherosclerosis by regulating angiogenesis, and different types of ginsenosides exert different pharmacological functions in inhibiting angiogenesis and promoting angiogenesis [ 9 ]. Yin and Yang originated from ancient China. It is based on the concept of duality and opposition that impacts one another in a subtle yet dynamic manner. In this framework, upward, outward and enhancing phenomena are usually classified as Yang while downward, inward and inhibiting phenomena are usually classified as Yin. As a result, the age-old philosophical doctrine can very well explain the regulatory effects of specific ginsenosides on angiogenesis. In this way, the inhibition of angiogenesis can be seen as Yin, while the promotion of angiogenesis will reflect Yang as opposites [ 10 ] ( as shown in Fig. 1 ).Although several reviews have described the angiogenic effects of ginsenosides, most focus on either pro- or anti-angiogenic activity alone. Few reviews have comprehensively integrated the bidirectional (Yin-Yang) regulation, structure-activity relationship, and context-dependent mechanisms of ginsenosides in angiogenesis. This narrative review fills this gap by providing a comprehensive overview of the dual effects and underlying molecular mechanisms, offering a more integrated understanding for future research. Fig. 1 The bidirectional regulatory effects of ginsenosides on angiogenesis. The mechanisms by which ginsenosides promote angiogenesis primarily include repairing nerve damage, improving ischemia-reperfusion injury, promoting bone regeneration and promote tissue repair and regeneration. The mechanisms by which ginsenosides inhibit angiogenesis primarily include improving retinal disorders, inhibition of inflammatory infiltration, improving cardiovascular and cerebrovascular diseases and suppress tumor growth and pathological angiogenesis. The bidirectional regulatory effects of ginsenosides on angiogenesis. The mechanisms by which ginsenosides promote angiogenesis primarily include repairing nerve damage, improving ischemia-reperfusion injury, promoting bone regeneration and promote tissue repair and regeneration. The mechanisms by which ginsenosides inhibit angiogenesis primarily include improving retinal disorders, inhibition of inflammatory infiltration, improving cardiovascular and cerebrovascular diseases and suppress tumor growth and pathological angiogenesis. This paper reviews the regulatory effects of various ginsenosides on angiogenesis, delving into their molecular mechanisms, signalling pathways, and potential applications in treating related diseases. It aims to systematically summarise the bidirectional regulatory role of ginsenosides in angiogenesis, thereby providing a robust theoretical foundation for future clinical applications based on ginsenoside-mediated angiogenesis regulation. Notably, the bidirectional angiogenic regulation of ginsenosides is also closely associated with gut microbiota metabolism. Gut microbiota mediates the metabolic transformation of ginsenosides into bioavailable active metabolites, which is a prerequisite for their subsequent regulatory effects on angiogenesis. Dysregulated gut microbiota may interfere with the expression of angiogenic factors (e.g., PI3K/Akt, MAPK), thereby modulating the Yin-Yang regulatory effects of ginsenosides on angiogenesis. As a narrative review, this article does not follow a systematic review methodology. The literature search was conducted using PubMed and Web of Science with search terms including “ginsenosides”, “angiogenesis”, “VEGF”, “HIF-1α”, and “signaling pathway”. Relevant studies were selected based on their relevance to the bidirectional regulation of angiogenesis by ginsenosides, with priority given to original research articles and mechanistic studies published in peer-reviewed journals. Given the narrative nature of this review, the selection of studies is not exhaustive, and the absence of a formal systematic methodology represents a limitation of this work.

These authors have no conflict of interest to declare.