Effect of Herbal Products and Their Active Constituents on Angiogenesis in Diabetic Wounds

Abstract

Angiogenesis plays a key role in tissue regeneration by delivering oxygen and nutrients to the injury site. In diabetes mellitus, various factors, including hyperglycemia, neuropathy, increased reactive oxygen species, and proinflammatory cytokines, decrease the levels of proangiogenic factors and increase levels of antiangiogenic factors, hamper angiogenesis, and hinder wound healing. Reconstruction of the vasculature of the wound bed is crucial for promoting diabetic wound healing and improving the quality of life of patients. Given the urgent need for innovative therapies to promote angiogenesis and accelerate the repair of diabetic wounds, researchers have increasingly focused on identifying herbal products and their active constituents with promising proangiogenic activity.

The aim of this review is to present verified data on the current knowledge on the effect of herbal products and their active constituents on angiogenesis processes in diabetic wounds.

The electronic databases were searched for articles published from 2014 to the present. The 38 articles comparing topically used herbal products/active constituents on angiogenesis in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected.

Herbal products and their active constituents are rich sources of novel angio-modulators that may affect the angiogenesis process in diabetic wound healing via different mechanisms of action, including stimulation of VEGF and HRMs and activation of the Nrf2, PI3K/AKT, and HIF-1α signaling pathways. Topical applications of herbal products and their active constituents, especially when incorporated into wound dressings, show promising proangiogenic activity and represent a potential alternative for the treatment of diabetic wounds.

Keywords

herbal products - active constituents - diabetic wounds - angiogenesis

Abbreviations

AM: alloxan monohydrate

DFU: diabetic foot ulcer

FGF: fibroblast growth factor

HIF-1: hypoxia-inducible factor-1

HRMs: hypoxia responsive microRNAs

HUVEC: human umbilical vein endothelial cells

Nrf2: nuclear factor erythroid 2–related factor 2

PDGF: platelet-derived growth factor

PDGFRα : platelet-derived growth factor receptor alpha

PI3K/AKT: Activated phosphatidylinositol 3 kinase/Protein kinase B

STZ: streptozotocin

TES: tissue engineering scaffolds

TGF-β : transforming growth factor β

VEGF: vascular endothelial growth factor1
 

Introduction

Diabetic patients have a reduced ability to metabolize glucose, which leads to hyperglycemic conditions [1]. High blood sugar levels in diabetic patients can lead to damage to small blood vessels, known as microangiopathy, which can further reduce blood flow to the wound site and decrease the oxygen and nutrient supply to the wound site, making diabetic wounds more difficult to repair [2], [3]. Local ischemia due to microvascular complications, impaired angiogenesis, an irregular inflammatory response, tissue oxidative stress, impaired fibroblast and keratinocytes migration and proliferation, and impaired production of cytokines and growth factors are the main factors that disturb the diabetic wound healing process [4]. Impaired wound healing in diabetic patients may lead to serious complications, such as a high risk of bacterial infection, gangrene, limb amputation, sepsis, and even death [5].

Angiogenesis (or neovascularization) is a critical process in diabetic wound healing, including the formation of a new capillary network (microvascular) in response to hypoxia (oxygen deprivation), providing skin tissues with nutrients and oxygen and supporting skin structure formation [6]. The hypoxic conditions in diabetes induce macrophages to secrete proangiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), fibroblast growth factor (FGF), and cytokines involved in the control of various aspects of angiogenesis [7], [8], [9]. VEGF is one of the key proangiogenic factors in diabetic wounds, and its production occurs following hypoxia and hyperglycemia. Hypoxia following injury activates hypoxia-inducible factor-1 (HIF-1), which promotes angiogenesis by upregulating the expression of target genes such as VEGF-A [10], whereas hyperglycemia induces indirect VEGF overexpression mediated by TGF-β [11]. Chronic, nonhealing diabetic wounds are closely related to poor vascular networks. It seems that maintaining a balance between proangiogenic factors (HIF-1, VEGF, FGF, and angiopoietin-1) and antiangiogenic factors (pigment epithelium-derived factor, thrombospondin-1, endostatin, and angiostatin) may be crucial during the diabetic wound healing process [12], [13], [14]. The reconstruction of the vasculature of the wound bed via the promotion of angiogenesis may be key to improving the treatment of diabetic wounds.

Some herbal products and their active constituents affect diabetic wound healing activities through antioxidant, antimicrobial, and anti-inflammatory activities, stimulation of angiogenesis, production of cytokines and growth factors, and fibroblast and keratinocyte migration and proliferation [15], [16]. Herbal products and their active constituents with promising proangiogenic activity may be recognized as innovative therapies to accelerate the repair of diabetic wounds.

The aim of this review is to present verified data on the current knowledge on the effect of herbal products and their active constituents on angiogenesis processes in diabetic wounds.

Methods

A comprehensive search of the PubMed and Google Scholar databases was conducted for articles published between 2014 and the present. Search terms included “herbal products with proangiogenic effect”, “the effect of herbal products on angiogenesis in diabetic wounds”, and “topically used herbal products on angiogenesis in diabetic wounds”. A citation-based manual search was also undertaken to identify further relevant literature.

Animal and human studies examining the effects of topically applied herbal products on angiogenesis in diabetic wound healing were included in the review. Studies investigating alternative routes of administration of herbal products (e.g., oral and systemic) other than topical application in diabetic wound healing were excluded. Additionally, studies evaluating angiogenesis effects of herbal products in non-diabetic models were excluded. Moreover, publications in languages other than English were excluded.

Herbal products and their active constituents with pro-angiogenic activity used for diabetic wound healing

Herbal products and their active constituents may promote angiogenesis [17]. Some animal- and human-based studies have shown that the use of herbal products and their active constituents with proangiogenic activity may be promising approaches for diabetic wound healing and tissue repair.

Animal-based studies

Herbal products with proangiogenic activity used for diabetic wound healing are shown in [Table 1]. Camellia sinensis [20], Chebulae fructus immaturus [21], Gynura divaricate [22], Moringa oleifera [23], mixtures of Acorus calamus, Angelica dahurica, Angelicae biseratae, Bauhinia purpurea, Paeonia lactiflora, and Paeoniae rubrae [18], and mixed powders of Agrimonia pilosa, Boswellia carteri, Nelumbo nucifera, and Pollen typhae [19] promote angiogenesis and vascular remodeling in the diabetic wounds of rats and mice.

Table 1 Herbal products with proangiogenic activity used for diabetic wound healing in animal-based studies.

Herbal products	Model of the study	Pharmacological data	Effect	Mechanism	Ref
AM: alloxan monohydrate; HIF-1α: hypoxia-inducible factor 1α; STZ: streptozotocin; VEGF: vascular endothelial growth factor
Acorus calamus, Angelica dahurica, Angelicae biseratae, Bauhinia purpurea, Paeonia lactiflora, Paeoniae rubrae	STZ-induced diabetic rats	mixture of B. purpurea (40%), A. biseratae (24%), P. rubrae and P. lactiflora (16%), A. calamus (12%), A. dahurica (8%) positive control: Kangfuxin solution negative control: 0.9% Saline treatment: once a day for 15 days	promote vascular renewal	VEGF	[18]
Agrimonia pilosa, Boswellia carteri, Nelumbo nucifera, Pollen typhae	STZ-induced diabetic C57BL/6 mice	mixed powders of A. pilosa, N. nucifera, B. carteri, P. typhae control: untreated group treatment: once a day for 21 days	promote vascularization	VEGF	[19]
Camellia sinensis	AM-induced diabetic rats	0.6% green tea methanolic extract negative control: Vaseline positive control: 5%w/w povidone iodine treatment: twice daily till the complete healing	promote angiogenesis and vascular remodeling	HRMs	[20]
Chebulae fructus	db/db mouse	Chebulae fructus extract treatment: 100 µL daily for 11 days	promote angiogenesis and formation of blood vessels	PI3K/AKT and HIF-1α signaling pathways	[21]
Gynura divaricate	STZ-induced diabetic rats	100 mg/mL G. divaricate extract negative control: 100 µL PBS treatment: 100 µL daily for 14 days	promote angiogenesis	Nrf2 signaling pathway	[22]
Moringa oleifera	STZ-induced diabetic rats	0.5%, 1%, and 2% w/w aqueous fraction of M. oleifera positive control: 1% w/w silver sulfadiazine treatment: once a day for 21 days	increase VEGF in wound tissue	VEGF	[23]

The active constituents isolated from herbal products with proangiogenic activity used for diabetic wound healing are shown in [Table 2]. The active constituents isolated from ginseng-20(S)-protopanaxadiol [24], [25], Lithospermum erythrorhizon-shikonin [28], β-sitosterol [26], and resveratrol [27] stimulate angiogenesis and neovascularization in the diabetic wounds of rats and mice.

Table 2 Active constituents isolated from herbal products with proangiogenic activity used for diabetic wound healing in animal-based studies.

Herbal products	Model of the study	Pharmacological data	Effect	Mechanism	Ref
HIF-1α: hypoxia-inducible factor 1α; HUVECs: human umbilical vein endothelial cells; STZ: streptozotocin; VEGF: vascular endothelial growth factor
20(S)-protopanaxadiol from Ginseng	STZ-induced diabetic BALB/c mice	25 µM 20(S)-protopanaxadiol negative control: PBS treatment: daily for 10 days	increase tube formation activity in HUVECs	VEGF	[24]
20(S)-protopanaxadiol from Panax notoginseng	leptin receptor-deficient (Leprdb/JNju, db/db) mice	15 µl 20(S)-protopanaxadiol (PPD) (0.6, 6, and 60 mg/ml) negative control: PBS treatment: every other day for 14 days	promote angiogenesis	PI3K/AKT and HIF-1α signaling pathways	[25]
β-sitosterol	STZ-induced diabetic rats	β-sitosterol group, β-sitosterol + inhibitor group (HIF-1α inhibitor – 2-methoxyestradiol) negative control: 0.9% saline treatment: once a day (50 µM)	promote neovascularization	VEGF	[26]
resveratrol	STZ-induced diabetic rats	20 µM resveratrol solution (100 µL injection) negative control: sterile saline positive control: 10 µM Ferrostatin solution (100 µL injection) treatment: every 3 days for 14 days	promote angiogenesis	Nrf2 signaling pathway	[27]
shikonin from Lithospermum erythrorhizon	STZ-induced diabetic rats	0, 20, and 40 µM shikonin control: nondiabetic rats treatment: 21 days	promote angiogenesis	VEGF	[28]

Human-based studies

Compared to many animal studies, there is one clinical trial describing the effect of herbal products with angiogenic activity on wound healing in diabetic patients. This research is based on the diabetic foot ulcer (DFU) model, which is associated with neuropathy, peripheral vascular disease, and chronic nonhealing wounds [29]. High glucose levels destroy nerve fibers, reduce the size of capillaries, and accelerate atherosclerosis and vasoconstriction, leading to arterial blockage and the formation of DFUs [30]. DFU treatment usually requires wound debridement, pressure offloading, glycemic control, and surgical interventions.

Topical application of Actindia deliciosa (kiwi fruit) resulted in a reduction in wound area or the complete healing of DFU in 17 patients treated with pure extract twice daily for 21 days in a randomized clinical trial [31]. Moreover, significantly increased levels of angiogenesis and vascularization were detected in the kiwifruit-treated patients. It is worth mentioning that this disproportion between the number of preclinical studies on animals and clinical trials has many reasons, including primarily regulatory and ethical barriers, high cost, organizational challenge, patient recruitment and their appropriate selection, and changes related to scaling doses from small animals to humans. Moving to clinical trials requires extensive documentation and regulatory approval, and safety concerns often lead to delays, additional studies, or trial redesigns. Also, ethical standards for human testing (e.g., informed consent and risk minimization) are much more stringent. Clinical trials, even at Phase I, are significantly more expensive than preclinical studies. High costs require strong justification from robust preclinical data, which is often lacking. Therefore, successful translation requires more predictive preclinical models, stronger collaboration across disciplines, and strategic planning for human application early in development.

Robust regulatory engagement and funding support, and understanding and addressing these challenges, are essential to improve the efficiency of biomedical innovation and ultimately deliver better treatments to patients.

Herbal products and their active constituents with pro-angiogenic activity loaded in dressings used for diabetic wound healing

The most popular angiogenesis-enhancing drug delivery systems based on herbal products ([Table 3]) and their active constituents ([Table 4]) for diabetic wound healing are ointments, hydrogels, nanofibers, scaffolds, and, recently, exosomes.

Table 3 Herbal-product-loaded dressings with proangiogenic activity used for diabetic wound healing in animal-based studies.

Herbs/active constituent	Model of the study	Pharmacological data	Effect	Mechanism	Ref
HUVEC: human umbilical vein endothelial cells; PDGFRα; platelet-derived growth factor receptor alpha; STZ: streptozotocin; TGF-β: transforming growth factor β; VEGF: vascular endothelial growth factor
Catha edulis	STZ-induced diabetic rats	C. edulis extract-loaded polycaprolacton/gelatin scaffolds control: nontreated group treatment: every 3 days for 14 days	increase VEGF	VEGF	[32]
Crocus sativus	STZ-induced diabetic NMRI mice	saffron (C. sativus) petals extract ointment positive control: Purilon® Gel (Coloplast) treatment: once a day for 14 days	enhance vascularity in tissue	VEGF	[33]
Ginseng	B6.BKS(D)-Lepr db/J (db/db) mice	100 µg/ml and 200 µg/ml exosomes derived from ginseng root (GExos) negative control: 100 µl of PBS treatment: once a day for 16 days	promote angiogenesis; nascent vessel network reconstruction	VEGF	[34]
Hypericum perforatum	STZ-induced diabetic rats	5% and 10% H. perforatum gel negative control: gel base treatment: once a day for 15 days	promote revascularization	VEGF	[35]
Malva sylvestris	STZ-induced diabetic rats	nanofibers of polyurethane and carboxymethyl cellulose (PU/CMC) with 15% w/w M. sylvestris extract negative control: gauze bandage and PU/CMC treatment: once a day for 14 days	increased neovascularization	VEGF	[36]
Phaleria macrocarpa	STZ-induced diabetic rats	2.5%, 5% and 10% P. macrocarpa extract ointment treatment: one daily for 7 days	promote angiogenesis	VEGF	[37]
Phyllanthus emblica	STZ-induced diabetic BALB/C mice	100% P. emblica extract (PE) cream; 5% simvastatin (SIM) cream; combination of 100% PE + 5% SIM in cream negative control: vehicle cream treatment: once a day for 14 days	promote angiogenesis	VEGF	[38]
Pomegranate peel extract	STZ-induced diabetic mice	citric acid cross-linked pomegranate peel extract-loaded pH-responsive β-dyclodextrin/carboxymethyl tapioca starch hydrogel negative control: standard formulation treatment: once every 24 h for 15 days	promote angiogenesis	VEGF	[39]
Rhubarb	mice type-2 diabetic (db/db)	chitosan/silk fibroin sponge scaffold loaded with rhubarb charcoal treatment: 14 days	increase neovascularization	VEGF	[40]
Teucrium polium	STZ-induced diabetic rats	0,5 g chitosan nanoparticle-loaded of T. polium hydrogel negative control: vehicle chitosan nanoparticle hydrogel positive control: 0.5 g of T. polium hydrogel/0.5 g of Mebo ointment (Gulf Pharmaceutical Industries Julphar) treatment: every day for 21 days	pro-angiogenic capabilities	VEGF	[41]
Xanthium strumarium	mice	0.1 or 1 mg/mL X. strumarium/gelatin methacryloyl-based hydrogels treatment: 21 days	promote angiogenesis	VEGF	[42]

Table 4 Active constituent-loaded dressings with proangiogenic activity used for diabetic wound healing in animal-based studies.

Herbs/active constituent	Model of the study	Pharmacological data	Effect	Mechanism	Ref
HIF-1α: hypoxia-inducible factor 1α; HUVECs: human umbilical vein endothelial cells; STZ: streptozotocin; VEGF: vascular endothelial growth factor
arnebin-1 from Arnebia euchroma	AM-induced diabetic rats	0.1% arnebin-1 ointment negative control: vehicle ointment treatment: once a day for 7 days	pro-angiogenic effect via tube formation	VEGF	[43]
astragaloside IV from Astragalus membranaceus	high-fat-diet rats	astragaloside IV (ASIV) exosomes (ASIV-EXO) in PF–PEG hydrogel negative control: sterile gauze/ASIV-EXO treatment: 14 days	promote angiogenesis	Nrf2 signaling pathway	[44]
curcumin	high-fat-, high-sugar-diet rats	zeolitic imidazolate framework-8 with mixture of curcumin with methylcellulose/carboxymethyl chitosan thermosensitive hydrogel negative control: PBS treatment: once a day for 14 days	promote angiogenesis	VEGF	[45]
curcumin from Curcuma longa	STZ-induced diabetic rats	curcumin hydrogel treatment: replaced every 2 days for 16 days	promote blood vessels growth, early angiogenesis	VEGF	[46]
curcumin from Curcuma longa	STZ-induced diabetic rats	curcumin-loaded gum tragacanth/poly(ε-caprolactone) electrospun nanofibers treatment: for 15 days	promote angiogenesis	VEGF	[47]
eugenol from lilacs	STZ-induced diabetic rats	0.5% and 1% eugenol-loaded polyurethane gelatin dressing negative control: polyurethane gelatin dressing without eugenol blank group: sterile gauze	stimulates the growth of HUVECs	VEGF	[48]
hydroxysafflor yellow A (HSYA) from Carthamus tinctorius	STZ-induced diabetic rats	HSYA and deferoxamine (HSYA/DFO) in chitosan/gelatin hydrogels 5 : 5 negative control: PBS/hydrogel base/HSYA and DFO solution; treatment: once a day for solutions/once every 2 days for hydrogel for 16 days	promote angiogenesis	VEGF	[49]
mangiferin	STZ-induced diabetic rats	5.0 and 10.0 mg/mL mangiferin hydrogel negative control: PBS treatment: once a day for 14 days	promote angiogenesis	VEGF	[50]
polysaccharide from Astragali Radix	STZ-induced diabetic rats	Astragalus polysaccharide-loaded tissue engineering scaffolds (TES) negative control: TES alone treatment: 5 mg each, once a day	restore microcirculation	VEGF	[51]
polysaccharide from Curcuma zedoaria	STZ-induced diabetic rats	polysaccharide (ZWP) in chitosan/silk hydrogel sponge loaded with platelet-rich plasma (PRP) exosomes (PRP-Exos/ZWP) negative control: gauze with 100 µl PBS/chitosan/silk hydrogel group/chitosan/silk hydrogel sponge loaded with PRP-Exos treatment: wound dressings changed every 3 days for 15 days	promote angiogenesis	VEGF	[52]
polysaccharide from Dioscorea opposita	STZ-induced diabetic rats	D. opposita polysaccharide (DOP)-calcium carbonate microspheres hydrogel (PL−PVA/DOP-CaCO3) negative control: PL−PVA hydrogel/insulin- PL−PVA/DOP-CaCO3hydrogel positive control: ofloxacin gel treatment: every 48 h for 21 days	promote angiogenesis	VEGF	[53]
polysaccharide from Gastrodia elata	STZ-induced diabetic ICR mice	G. elata polysaccharide-based hydrogel embedded with microspheres negative control: vehicle gel treatment: once a day for 14 days	promote angiogenesis	VEGF	[54]
polysaccharide from Periplaneta americana	STZ-induced diabetic rats	hydrogel with polysaccharide P. americana negative control: hydrogel base positive control: Kangfuxin solution treatment: once daily for 15 days	promote angiogenesis	VEGF	[55]
salvianolic acid B from Salvia miltiorrhiza	STZ-induced diabetic rats	0%, 0.5%, 1.0%, 1.5% salvianolic acid B sodium alginate and gelatin scaffold negative control: Vaseline treatment: 14 days	increase VEGF	VEGF	[56]
tetramethylpyrazine from Ligusticum chuanxiong	STZ-induced diabetic C57BL/6 mice	250 µmol/L tetramethylpyrazine hydrogel positive control: Intrasite Gel (Smith&Nephew) treatment: 14 days	increase VEGF	VEGF	[57]
vicenin-2	STZ-induced diabetic rats	12.5, 25, and 50 µM vicenin-2 hydrocolloid film (sodium alginate) positive control: 316 µM allantoin film treatment: every day for 14 days	increase blood vessels	VEGF	[58]

The most common form of carrier of active compounds for the treatment of diabetic wounds is ointment. Ointments with saffron (C. sativus) petal extract [33], P. macrocarpa extract [37], P. emblica extract [38], and 0.1% arnebin-1 from A. euchroma [43] enhance angiogenesis via revascularization.

Hydrogels are the most attractive carriers of active compounds used to treat diabetic wounds. A hydrogel is a gel composed usually of one or more polymers suspended in water. Hydrogels can absorb wound exudate, maintain a moist environment, exchange gas, and provide thermal insulation. Hydrogels are also easy to remove from the wound surface and are painless in changing the dressings for the patient. Moreover, hydrogels may have antibacterial properties [59]. H. perforatum extract hydrogel [35], pomegranate peel extract hydrogel [39], X. strumarium extract hydrogel [42], astragaloside IV from A. membranaceus hydrogel [44], curcumin from C. longa hydrogel [45], [46], hydroxysafflor yellow A from C. tinctorius hydrogel [49], mangiferin hydrogel [50], polysaccharide from D. opposite hydrogel [53], polysaccharide from G. elata hydrogel [54], polysaccharide from P. americana hydrogel [55], tetramethylpyrazine from L. chuanxiong hydrogel [57], and chitosan nanoparticle-loaded T. polium hydrogel [41] promote angiogenesis in diabetic wounds.

Compared with other dressing types, nanofiber dressings have been shown to promote the adhesion, proliferation, and migration of fibroblasts and to accelerate the diabetic wound healing process [60]. Moreover, nanofibers possess small pores but high porosity, which ensures high effectiveness of the microbial barrier, as well as excellent moisture and air permeability properties [61]. These parameters make nanofibers a great drug delivery system for diabetic wound healing. Nanofibers of polyurethane and carboxymethyl cellulose with M. sylvestris extract [36] and curcumin-loaded gum tragacanth/poly(ε-caprolactone) electrospun nanofibers [47] promote angiogenesis and increase neovascularization activity in diabetic wounds.

Scaffolds play a major role as biomaterials for wound dressings because of their tissue regeneration properties and fluid absorption capacity [62]. C. edulis extract-loaded polycaprolactone/gelatin scaffolds [32], chitosan/silk fibroin sponge scaffolds loaded with rhubarb charcoal [40], Astragalus polysaccharide–loaded tissue engineering (TES) scaffolds [51], and salvianolic acid B from S. miltiorrhiza–loaded sodium alginate and gelatin scaffolds [56] increase neovascularization and increase the expression of VEGF in diabetic wounds.

Recently, interest in the use of exosomes and biomaterial-based exosomes in cutaneous wound treatment and regenerative medicine has increased. Exosomes are nanosized vesicles that are capable of regulating intercellular communication by releasing their contents into target cells, which promotes wound healing [63]. Their advantages, stability, biocompatibility, and low immunogenicity, make them promising substitutes for cell-based therapy, offering a more effective approach to promote diabetic wound healing [64]. Exosomes support diabetic wound healing by inhibiting inflammation and stimulating angiogenesis and collagen deposition [65]. Exosomes derived from ginseng roots [34], astragaloside IV (ASIV) exosomes (ASIV-EXOs) loaded in hydrogels [44], and polysaccharides from C. zedoaria in chitosan/silk hydrogel sponges loaded with platelet-rich plasma exosomes [52] promote angiogenesis and vessel network reconstruction in diabetic wounds.

Mechanism of action of herbal products and their active constituents used for diabetic wound healing on the angiogenesis processes

Angiogenesis can be divided into two main types, sprouting and intussusceptive angiogenesis, both of which occur after exposure to hypoxia and skin injury. Sprouting angiogenesis is the process of formation new blood vessels from pre-existing ones via (1) proteases degradation of capillary basement membrane, (2) endothelial cell migration and proliferation into the surrounding matrix and form solid sprouts connecting neighboring vessels, (3) tube formation, and (3) pericyte stabilization [66]. Intussusceptive angiogenesis is a type of blood vessel formation in which new vessels are created by splitting an existing vessel into two vessels through a flow-dependent mechanism initiated by a transluminal bridge of cell–cell contacts [67]. Sprouting angiogenesis involves the growth of new blood vessels in previously avascular tissues, while intussusceptive angiogenesis involves the splitting of existing vessels into smaller ones via adaptation of existing microvascular networks [68]. In terms of therapeutic intervention, sprouting and intussusceptive angiogenesis may be the primary targets for the treatment of diabetic wounds. Herbal products and their active constituents, which are rich sources of angio-modulators, may affect angiogenesis [17]. The VEGF, circulating hypoxia-responsive microRNA (HRM), nuclear factor erythroid 2–related factor 2 (Nrf2), and PI3K/AKT and HIF-1α signaling pathways are potent proangiogenic factors that promote angiogenesis in diabetic wounds ([Fig. 1]).

Fig. 1 Mechanism of action of herbal products and their active constituents on the angiogenesis processes in diabetic wounds.

VEGF

The major mechanisms of the proangiogenic action of herbal products and their active constituents are related mostly to VEGF-dependent signaling pathways. VEGF is one of the most potent proangiogenic factors that promotes all stages of angiogenesis via endothelial cell migration and proliferation, the spread into surrounding tissues, lumen formation, blood vessel maturation, and increased vascular permeability [69]. Cellular responses to VEGF are mediated mainly by the receptor tyrosine kinase VEGFR2 on the surface of endothelial cells in a paracrine manner [70]. VEGF gene expression can be modulated at the transcriptional level, and the VEGF promoter contains various binding sites for transcription factors, including HIF-1α [71]. In hypoxic conditions, HIF-1α hydroxylation is inhibited. Therefore, HIF-1α accumulates and translocates to the nucleus, where it forms a dimer with HIF-1β that binds to the VEGF promoter. HIF-1α binding to the VEGF promoter is essential for increased expression of target genes such as VEGF-A and the maximal VEGF mRNA transcription [72]. VEGF-A, the major isoform found in wounds, binds to its receptors on endothelial cells and stimulates the formation of new blood vessels [13].

Herbal products and their active constituents promote angiogenesis by increasing VEGF production through the modulation of HIF-1α [17]. The topical application of mixtures of the herbal extracts B. purpurea, A. biseratae, P. rubrae, P. lactiflora, A. calamus, and A. dahurica [18], mixed powders of A. pilosa, N. nucifera, B. carteri, and P. typhae [19], aqueous fractions of M. oleifera [23], and β-sitosterol [26] stimulated angiogenesis via the upregulation of VEGF. Some herbal products and their active constituents promote angiogenesis via increased VEGF production through the modulation of HIF-1α. Shikonin from L. erythrorhizon enhanced the mRNA expression of VEGFA and HIF-1α [28]. Hydroxysafflor yellow A and deferoxamine loaded in chitosan/gelatin hydrogels synergistically enhanced angiogenesis via the upregulation of HIF-1α expression [49]. The chitosan nanogel of T. polium enhances the expression of transforming growth factor beta1 (TGF-β1) and the angiogenic markers VEGFA and platelet-derived growth factor receptor alpha (PDGFRα) [41]. Topical application of C. edulis extract–loaded nanofibrous scaffolds [32], D. opposita polysaccharide (DOP)-calcium carbonate microsphere hydrogel (PL−PVA/DOP-CaCO₃ hydrogel) [53], mangiferin hydrogel [50], G. elata polysaccharide–based hydrogel [54], X. strumarium/gelatin methacryloyl–based hydrogels [42], C. sativus petal extract ointment [33], exosomes derived from ginseng root [34], H. perforatum gel [35], M. sylvestris extract nanofibers [36], P. macrocarpa extract ointment [37], P. emblica extract cream [38], citric acid crosslinked pomegranate peel extract–loaded pH-responsive β-dyclodextrin/carboxymethyl tapioca starch hydrogel [39], chitosan/silk fibroin sponge scaffold loaded with rhubarb charcoal [40], arnebin-1 ointment [43], curcumin hydrogels [45], [46], curcumin nanofibers [47], eugenol-loaded polyurethane gelatin dressing [48], polysaccharide from Astragali Radix [51], polysaccharide from C. zedoaria [52], polysaccharide from P. americana [55], salvianolic acid B sodium alginate and gelatin scaffold [56], tetramethylpyrazine from L. chuanxiong hydrogel [57], and vicenin-2 hydrocolloid [58] enhance impaired wound healing in diabetic wounds through upregulation of VEGF and accelerating the angiogenesis process.

HRMs

HRMs, including miR-21, miR-199a, miR-210, and miR-424, are potential molecular markers of angiogenesis in wounded skin tissues [73]. HRMs are induced by HIF1-α under hypoxia in the chronic wound healing process. The miR-424 is expressed to stabilize HIF1α, while miR-20b, miR-17~92, and miR-199a that target the HIF1α transcript are repressed to increase HIF1-α expression and transcription [74]. Camellia sinensis extract promotes angiogenesis and vascular remodeling via the molecular control of HRMs, including miR-21, miR-199a, miR-210, and miR-424, in diabetic and nondiabetic wounds [20]. These results support the functional role of HRMs as potential therapeutic targets in angiogenesis and vascular remodeling in wound healing in patients with diabetes.

PI3K/AKT and HIF-1α signaling pathways

Activated phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling is crucial in the repair processes of normal tissue and plays a critical role in the regeneration, remodeling, and reepithelialization of injured tissue [75], [76]. A lack of Akt1, a serine/threonine kinase, impairs VEGF expression, angiogenesis, and maturation of the vasculature and does not affect wound closure [77]. In turn, PI3K-dependent activation of AKT influences the activity of several pathways involved in cell proliferation, angiogenesis, senescence, apoptosis, and survival [78].

Some herbal products and their active constituents act on the PI3K/AKT and HIF-1α signaling pathways. Chebulae fructus immaturus extract improved angiogenesis through the PI3K/AKT and HIF-1α signaling pathways, ultimately promoting the healing of diabetic wounds [21]. Additionally, 20(S)-protopanaxadiol enhances angiogenesis via HIF-1α-mediated VEGF secretion by activating p70S6 kinase through the PI3K/Akt/mTOR and Raf/MEK/ERK signaling cascades and enhances wound healing in genetically diabetic mice [25].

Nrf2 signaling pathway

The role of Nrf2 in wound healing involves detecting ROS accumulation in injured and inflamed tissues and activating the antioxidant defense system [79]. Nrf2 activation stimulates the migration and proliferation of epithelial cells during diabetic wound healing and inhibits apoptosis [80]. These results suggest that Nrf2 deficiency also impairs angiogenesis due to prolonged inflammation and a lack of neovascularization mediators [81]. Nrf2 significantly influences angiogenesis through the Nrf2 markedly inhibiting the upregulation of VEGF [82]. Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through the PI3K/Akt signaling pathway in microvascular endothelial cells under hypoxic conditions [83]. Therefore, pharmacological activation of the Nrf2 pathway may modulate inflammation, granulation tissue, and vascular and neural function in diabetes.

G. divaricate extract exerts diabetic wound healing effects by activating the Nrf2 signaling pathway [22]. The VEGF, CD31, and VEGFR expression increased in the skin tissue of diabetic rats after treatment with G. divaricate extract, which increased HO-1, NQO-1, and Bcl-2 expression and downregulated Bax expression via activation of the Nrf2 signaling pathway. The Nrf2 signaling pathway attenuates oxidative stress and facilitates angiogenesis in diabetic wounds. Resveratrol promotes diabetic wound healing by inhibiting ferroptosis in vascular endothelial cells and activating angiogenesis via the Nrf2 signaling pathway [27]. Ferroptosis, a form of programmed cell death caused by disruption of iron homeostasis and ROS production [84], exacerbates damage in diabetic wounds, leading to delayed healing, while the concomitant use of resveratrol and ferroptosis (an inhibitor of ferrostatin-1) enhances diabetic wound healing and angiogenesis via increased expression of the Nrf2, VEGF, and CD31 proteins in vascular endothelial cells. Additionally, an astragaloside IV delivery system (PF−PEG@ASIV-EXO) hydrogel increased the expression of VEGF and CD31, promoting angiogenesis through the inhibition of ferroptosis and thereby accelerating the healing of diabetic wounds [44].

Limitations and future directions

Herbal products and their active constituents showed promoting effects on angiogenesis, which is essential for healing diabetic wounds. However, there are several limitations that affect their efficacy, including variability of the source and preparation of the plant raw material, lack of herbal products standardization, potential problems of toxicity, and allergenicity of herbal products, as well as product quality control. Different growing conditions, harvesting times, and extraction methods can affect the chemical profile of herbs and their therapeutic effect and batch-to-batch variability [85]. Moreover, unknown purity of herbal products, especially contaminants such as heavy metals and pesticides, are not listed in the formulation [86]. The lack of standardized dosages and concentrations of active ingredients in herbal products have an effect on inconsistent therapeutic outcomes and difficulty in reproducing effects across animal and human studies. Herbal extracts contain multiple compounds, making it hard to identify which specific constituents drive angiogenesis, which hinders mechanistic understanding and herbal drug development. Moreover, there is a strong and persistent belief among consumers that herbal agents, derived from “natural” plant sources, are inherently safe and free from adverse effects. However, literature data showed that some herbal products applied topically may cause edema, erythema, and allergic reactions, and several can be responsible for photosensitization [87], [88]. In many jurisdictions, there are no requirements to demonstrate the efficacy or safety of herbal products, nor centralized systems for monitoring or reporting adverse effects [89]. The increasing number of herbal remedies available for sale should prompt governments to regulate research that should be performed before such products are introduced to the market. Therefore, the standardization of herbal products, safety assessments, pharmacokinetic studies, quality control of herbal formulations, legal regulation, expansion of advanced delivery systems of active compounds (hydrogels, nanofibers, and exosomes) and their potential in clinical translation, and conducting large-scale and well-designed clinical trials of the effectiveness of herbal products become particularly important.

Conclusions

The difficulties associated with diabetic wound healing are related to many factors, such as wound infection, changes in inflammatory responses, failure of angiogenesis, and disturbed processes of cell proliferation and skin reconstruction. Angiogenesis, which is generally related to diabetic wound healing, is hampered by hyperglycemia, increased levels of ROS and proinflammatory cytokines (TNF-α and IL-1β), reduced levels of proangiogenic factors (VEGF, bFGF, and Ang-1), increased levels of antiangiogenic factors (TSP-1, endostatin, and angiostatin), altered extracellular matrix (ECM) composition, and neuropathy. Reconstruction of wound-bed blood vessels by promoting angiogenesis may be key to improving diabetic wound healing. Herbal products and their active constituents are rich sources of novel angio-modulators that may affect the angiogenesis process in diabetic wound healing via different mechanisms of action, including stimulation of VEGF and HRMs and activation of the Nrf2, PI3K/AKT, and HIF-1α signaling pathways. Topical applications of herbal products and their active constituents with promising proangiogenic activity loaded in dressings seem to be a good alternative for diabetic wounds treatment. The creation of such a system would be a significant advance in the treatment of diabetic wounds and would improve the quality of life of patients.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 06 July 2025

Accepted after revision: 30 October 2025

Accepted Manuscript online:
30 October 2025

Article published online:
17 November 2025