Sulfated oligosaccharide activates endothelial Notch for inducing macrophage-associated arteriogenesis to treat ischemic diseases.

Ischemic diseases lead to considerable morbidity and mortality, yet conventional clinical treatment strategies for therapeutic angiogenesis fall short of being impactful. Despite the potential of biomaterials to deliver pro-angiogenic molecules at the infarct site to induce angiogenesis, their efficacy has been impeded by aberrant vascular activation and off-target circulation. Here, we present a semisynthetic low-molecular sulfated chitosan oligosaccharide (SCOS) that efficiently induces therapeutic arteriogenesis with a spontaneous generation of collateral circulation and blood reperfusion in rodent models of hind limb ischemia and myocardial infarction. SCOS elicits anti-inflammatory macrophages' (Mφs') differentiation into perivascular Mφs, which in turn directs artery formation via a cell-to-cell communication rather than secretory factor regulation. SCOS-mediated arteriogenesis requires a canonical Notch signaling pathway in Mφs via the glycosylation of protein O-glucosyltransferases 2, which results in promoting arterial differentiation and tissue repair in ischemia. Thus, this highly bioactive oligosaccharide can be harnessed to direct efficiently therapeutic arteriogenesis and perfusion for the treatment of ischemic diseases.

Therapeutic Effects of Anti-Inflammatory and Anti-Oxidant Nutritional Supplementation in Retinal Ischemic Diseases.

Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases.

Integrative analyses and validation of ferroptosis-related genes and mechanisms associated with cerebrovascular and cardiovascular ischemic diseases.

BACKGROUND: There has been a gradual increase in the occurrence of cardiovascular and cerebrovascular ischemic diseases, particularly as comorbidities. Yet, the mechanisms underlying these diseases remain unclear. Ferroptosis has emerged as a potential contributor to cardio-cerebral ischemic processes. Therefore, this study investigated the shared biological mechanisms between the two processes, as well as the role of ferroptosis genes in cardio-cerebral ischemic damage, by constructing co-expression modules for myocardial ischemia (MI) and ischemic stroke (IS) and a network of protein-protein interactions, mRNA-miRNA, mRNA-transcription factors (TFs), mRNA-RNA-binding proteins (RBPs), and mRNA-drug interactions. RESULTS: The study identified seven key genes, specifically ACSL1, TLR4, ADIPOR1, G0S2, PDK4, HP, PTGS2, and subjected them to functional enrichment analysis during ischemia. The predicted miRNAs were found to interact with 35 hub genes, and interactions were observed between 11 hub genes and 30 TF transcription factors. Additionally, 10 RBPs corresponding to 16 hub genes and 163 molecular compounds corresponding to 30 hub genes were identified. This study also clarified the levels of immune infiltration between MI and IS and different subtypes. Finally, we identified four hub genes, including TLR4, by using a diagnostic model constructed by Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis; ADIPOR1, G0S2, and HP were shown to have diagnostic value for the co-pathogenesis of MI and cerebral ischemia by both validation test data and RT-qPCR assay. CONCLUSIONS: To the best our knowledge, this study is the first to utilize multiple algorithms to comprehensively analyze the biological processes of MI and IS from various perspectives. The four hub genes, TLR4, ADIPOR1, G0S2, and HP, have proven valuable in offering insights for the investigation of shared injury pathways in cardio-cerebral injuries. Therefore, these genes may serve as diagnostic markers for cardio-cerebral ischemic diseases.

Application of stem cell-derived exosomes in ischemic diseases: opportunity and limitations.

Ischemic diseases characterized by an insufficient blood flow that leads to a decrease in oxygen and nutrient uptake by cells have emerged as an important contributor to both disability and death worldwide. Up-regulation of angiogenesis may be a key factor for the improvement of ischemic diseases. This article searched articles in PubMed with the following keywords: stem cells, exosomes, angiogenesis, ischemic diseases either alone or in grouping form. The most relevant selected items were stem cell-derived exosomes and ischemic diseases. A growing body of evidence indicates that stem cells produce exosomes, which is the novel emerging approach to cell-to-cell communication and offers a new standpoint on known therapeutic strategies of ischemic diseases. Exosomes transport biological molecules such as many types of proteins, RNAs, DNA fragments, signaling molecules, and lipids between cells. Different stem cells release exosomes representing beneficial effects on ischemic diseases as they promote angiogenesis both in vitro and in vivo experiments. Application of exosomes for therapeutic angiogenesis opened new opportunities in the regenerative medicine, however, some limitations regarding exosomes isolation and application remain concerned. In addition, most of the experiments were conducted in preclinical and therefore translation of these results from bench to bed requires more effort in this field. Exosomes from stem cells are a promising tool for the treatment of ischemic diseases. In addition, translation of pre-clinic results into clinic needs further studies in this field.

Protective effects of natural compounds against oxidative stress in ischemic diseases and cancers via activating the Nrf2 signaling pathway: A mini review.

Oxidative stress, an imbalance between reactive oxygen species and antioxidants, has been seen in the pathological states of many disorders such as ischemic diseases and cancers. Many natural compounds (NCs) have long been recognized to ameliorate oxidative stress due to their inherent antioxidant activities. The modulation of oxidative stress by NCs via activating the Nrf2 signaling pathway is summarized in the review. Three NCs, ursolic acid, betulinic acid, and curcumin, and the mechanisms of their cytoprotective effects are investigated in myocardial ischemia, cerebral ischemia, skin cancer, and prostate cancer. To promote the therapeutic performance of NCs with poor water solubility, the formulation approach, such as the nano drug delivery system, is elaborated as well in this review.

How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment?

Exosomes, as natural occurring vesicles, play highly important roles in the behavior and fate of ischemic diseases and different tumors. Secretion, composition, and function of exosomes are remarkably influenced by hypoxia in ischemic diseases and tumor microenvironment. Exosomes secreted from hypoxic cells affect development, growth, angiogenesis, and progression in ischemic diseases and tumors through a variety of signaling pathways. In this review article, we discuss how hypoxia affects the quantity and quality of exosomes, and review the mechanisms by which hypoxic cell-derived exosomes regulate ischemic cell behaviors in both cancerous and noncancerous cells.

Oleuropein attenuates hydrogen peroxide-induced autophagic cell death in human adipose-derived stem cells.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with self-renewing properties; thus, transplanting functionally enhanced MSCs might be a promising strategy for cell therapy against ischemic diseases. However, extensive oxidative damage in ischemic tissue affects the cell fate of transplanted MSCs, eventually resulting in cell damage and autophagic cell death. Oleuropein (OLP) is a bioactive compound isolated from olives and olive oil that harbors antioxidant properties. This study aimed to investigate the potential cytoprotective effects of OLP against oxidative stress and autophagic cell death in MSCs. We found that short-term priming with OLP attenuated H2O2-induced apoptosis by regulating the pro-apoptotic marker Bax and the anti-apoptotic markers Bcl-2 and Mcl-1. Notably, OLP inhibits H2O2 -induced autophagic cell death by modulating autophagy-related death signals, including mTOR (mammalian target of rapamycin), ULK1 (unc-51 like autophagy activating kinase 1), Beclin-1, AMPK (AMP-activated protein kinase), and LC3 (microtubule-associated protein 1a/1b-light chain 3). Our data suggest that OLP might reduce H2O2-induced autophagy and cell apoptosis in MSCs by regulating both the AMPK-ULK axis and the Bcl-2-Mcl-1 axis. Consequently, short-term cell priming with OLP might enhance the therapeutic effect of MSCs against ischemic vascular diseases, which provides an important potential improvement for emerging therapeutic strategies.

The Role of Circular RNAs in Cerebral Ischemic Diseases: Ischemic Stroke and Cerebral Ischemia/Reperfusion Injury.

Cerebral ischemic diseases including ischemic stroke and cerebral ischemia reperfusion injury can result in serious dysfunction of the brain, which leads to extremely high mortality and disability. There are no effective therapeutics for cerebral ischemic diseases to date. Circular RNAs are a kind of newly investigated noncoding RNAs. It is reported that circular RNAs are enriched in multiple organs, especially abundant in the brain, which indicates that circular RNAs may be involved in cerebral physiological and pathological processes. In this chapter, we will firstly review the pathophysiology, underlying mechanisms, and current treatments of cerebral ischemic diseases including ischemic stroke and cerebral ischemia/reperfusion injury. Secondly, the characteristics and function of circular RNAs will be outlined, and then we are going to introduce the roles circular RNAs play in human diseases. Finally, we will summarize the function of circular RNAs in cerebral ischemic diseases.

[Mesenterointestinocolonovascular arterial ischemic disease: guidelines of the angiology section of Slovak Medical Chamber (AS SMC, 2013)]. / Mezentériointestinokolonovaskulárna artériová ischemická choroba Odporúcania Sekcie angiológov Slovenskej lekárskej komory (2013).

Organovascular arterial ischemic diseases (cardiovascular, cerebrovascular, extremitovascular, renovascular, genitovascular, pulmovascular, mesenterovascular, dermovascular, oculovascular, otovascular, stomatovascular etc.) are an important manifestations of systemic atherosclerosis and other arterial diseases of vascular system (arteriolosclerosis/arteriolonecrosis; diabetic macroangiopathy; diabetic microangiopathy; Mönckeberg´s mediosclerosis/mediocalcinosis; arteritis - vasculitis; syndromes of arterial compression; fibromuscular dysplasia; cystic adventitial degeneration; arterial thrombosis; arterial embolism/thromboembolism; traumatic and posttraumatic arteriopathies; physical arteriopathies; chemical and toxic arteriopathies; iatrogenic arterial occlusions; dissection of aorta and of arteries; coiling; kinking; complicated arterial aneurysms; arteriovenous fistula, rare vascular diseases). Key clinical-etiology-anatomy-pathophysiology (CEAP) aspects of the mesenteriovascular arterial ischemic diseases are discussed in this article (project Vessels).

O-GlcNAcylation in ischemic diseases.

Protein glycosylation is an extensively studied field, with the most studied forms being oxygen or nitrogen-linked N-acetylglucosamine (O-GlcNAc or N-GlcNAc) glycosylation. Particular residues on proteins are targeted by O-GlcNAcylation, which is among the most intricate post-translational modifications. Significantly contributing to an organism's proteome, it influences numerous factors affecting protein stability, function, and subcellular localization. It also modifies the cellular function of target proteins that have crucial responsibilities in controlling pathways related to the central nervous system, cardiovascular homeostasis, and other organ functions. Under conditions of acute stress, changes in the levels of O-GlcNAcylation of these proteins may have a defensive function. Nevertheless, deviant O-GlcNAcylation nullifies this safeguard and stimulates the advancement of several ailments, the prognosis of which relies on the cellular milieu. Hence, this review provides a concise overview of the function and comprehension of O-GlcNAcylation in ischemia diseases, aiming to facilitate the discovery of new therapeutic targets for efficient treatment, particularly in patients with diabetes.

Case Report: COVID-19 exacerbates acute lower limb ischemia in patients with popliteal artery entrapment syndrome.

Non-traumatic lower limb ischemic diseases are extremely rare among young people. Clinically, they are mainly seen in the form of popliteal artery entrapment syndrome (PAES). In addition, with the prevalence of COVID-19 infection, more and more studies report that COVID-19 infection may lead to arteriovenous thrombosis, which could cause lower limb ischemia. This case reported that a 31-year-old male amateur football player who developed intermittent claudication after recovering from COVID-19. After 2 months of consultation, he was ultimately diagnosed with PAES. As is well known, PAES is mostly caused by long-term compression of the popliteal artery by abnormal anatomical structures, resulting in thickening of the vascular outer membrane and progression of the disease until intimal damage and thrombosis, leading to lower limb ischemia. During the progression of the disease, there may be multiple factors that accelerate its progression. Therefore, combined with the patient's clinical history and related studies on confirmed thrombosis caused by COVID-19, we can infer that COVID-19 could accelerate the occurrence of PAES.

Peptide OM-LV20 promotes arteriogenesis induced by femoral artery ligature via the miR-29b-3p/VEGFA axis.

BACKGROUND AND AIMS: Therapeutic arteriogenesis is a promising direction for the treatment of ischemic disease caused by atherosclerosis. However, pharmacological or biological approaches to stimulate functional collateral vessels are not yet available. Identifying new drug targets to promote and explore the underlying mechanisms for therapeutic arteriogenesis is necessary. METHODS: Peptide OM-LV20 (20 ng/kg) was administered for 7 consecutive days on rat hindlimb ischemia model, collateral vessel growth was assessed by H&E staining, liquid latex perfusion, and specific immunofluorescence. In vitro, we detected the effect of OM-LV20 on human umbilical vein endothelial cells (HUVEC) proliferation and migration. After transfection, we performed quantitative real-time polymerase chain reaction, in situ-hybridization and dual luciferase reporters to assessed effective miRNAs and target genes. The proteins related to downstream signaling pathways were detected by Western blot. RESULTS: OM-LV20 significantly increased visible collateral vessels and endothelial nitric oxide synthase (eNOS), together with enhanced inflammation cytokine and monocytes/macrophage infiltration in collateral vessels. In vitro, we defined a novel microRNA (miR-29b-3p), and its inhibition enhanced proliferation and migration of HUVEC, as well as the expression of vascular endothelial growth factor A (VEGFA). OM-LV20 also promoted migration and proliferation of HUVEC, and VEGFA expression was mediated via inhibition of miR-29b-3p. Furthermore, OM-LV20 influenced the protein levels of VEGFR2 and phosphatidylinositol3-kinase (PI3K)/AKT and eNOS in vitro and invivo. CONCLUSIONS: Our data indicated that OM-LV20 enhanced arteriogenesis via the miR-29b-3p/VEGFA/VEGFR2-PI3K/AKT/eNOS axis, and highlighte the application potential of exogenous peptide molecular probes through miRNA, which could promote effective therapeutic arteriogenesis in ischemic conditions.

Preconditioning of MSCs for Acute Neurological Conditions: From Cellular to Functional Impact-A Systematic Review.

This systematic review aims to gather evidence on the mechanisms triggered by diverse preconditioning strategies for mesenchymal stem cells (MSCs) and their impact on their potential to treat ischemic and traumatic injuries affecting the nervous system. The 52 studies included in this review report nine different types of preconditioning, namely, manipulation of oxygen pressure, exposure to chemical substances, lesion mediators or inflammatory factors, usage of ultrasound, magnetic fields or biomechanical forces, and culture in scaffolds or 3D cultures. All these preconditioning strategies were reported to interfere with cellular pathways that influence MSCs' survival and migration, alter MSCs' phenotype, and modulate the secretome and proteome of these cells, among others. The effects on MSCs' phenotype and characteristics influenced MSCs' performance in models of injury, namely by increasing the homing and integration of the cells in the lesioned area and inducing the secretion of growth factors and cytokines. The administration of preconditioned MSCs promoted tissue regeneration, reduced neuroinflammation, and increased angiogenesis and myelinization in rodent models of stroke, traumatic brain injury, and spinal cord injury. These effects were also translated into improved cognitive and motor functions, suggesting an increased therapeutic potential of MSCs after preconditioning. Importantly, none of the studies reported adverse effects or less therapeutic potential with these strategies. Overall, we can conclude that all the preconditioning strategies included in this review can stimulate pathways that relate to the therapeutic effects of MSCs. Thus, it would be interesting to explore whether combining different preconditioning strategies can further boost the reparative effects of MSCs, solving some limitations of MSCs' therapy, namely donor-associated variability.

Loss of TET2 impairs endothelial angiogenesis via downregulating STAT3 target genes.

BACKGROUND: Ischemic diseases represent a major global health care burden. Angiogenesis is critical in recovery of blood flow and repair of injured tissue in ischemic diseases. Ten-eleven translocation protein 2 (TET2), a member of DNA demethylases, is involved in many pathological processes. However, the role of TET2 in angiogenesis is still unrevealed. METHODS: TET2 was screened out from three DNA demethylases involved in 5-hydroxylmethylcytosine (5-hmC) regulation, including TET1, TET2 and TET3. Knockdown by small interfering RNAs and overexpression by adenovirus were used to evaluate the role of TET2 on the function of endothelial cells. The blood flow recovery and density of capillary were analyzed in the endothelial cells-specific TET2-deficient mice. RNA sequencing was used to identify the TET2-mediated mechanisms under hypoxia. Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and glucosylated hydroxymethyl-sensitive-qPCR (GluMS-qPCR) were further performed to reveal the interaction of TET2 and STAT3. RESULTS: TET2 was significantly downregulated in endothelial cells under hypoxia and led to a global decrease of 5-hmC level. TET2 knockdown aggravated the hypoxia-induced dysfunction of endothelial cells, while TET2 overexpression alleviated the hypoxia-induced dysfunction. Meanwhile, the deficiency of TET2 in endothelial cells impaired blood flow recovery and the density of capillary in the mouse model of hindlimb ischemia. Mechanistically, RNA sequencing indicated that the STAT3 signaling pathway was significantly inhibited by TET2 knockdown. Additionally, Co-IP, ChIP-qPCR and GluMS-qPCR further illustrated that STAT3 recruited and physically interacted with TET2 to activate STAT3 target genes. As expected, the effects of TET2 overexpression were completely suppressed by STAT3 silencing in vitro. CONCLUSIONS: Our study suggests that the deficiency of TET2 in endothelial cells impairs angiogenesis via suppression of the STAT3 signaling pathway. These findings give solid evidence for TET2 to be a therapeutic alternative for ischemic diseases.

A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis.

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr2+ and SiO3 2- ions within 28 days. The biological activity of the bioactive ions released from the hydrogels was verified on HUVECs, SMCs, C2C12 and Raw 264.7 cells in vitro, and the therapeutic effect of the hydrogel was confirmed using C57BL/6 mouse model of femoral artery ligation in vivo. The results showed that the composite hydrogel stimulated angiogenesis, developed new collateral capillaries, and re-established the blood supply. In addition, the bioactive hydrogel directly promoted the expression of muscle-regulating factors (MyoG and MyoD) to protect skeletal muscle from necrosis, inhibited M1 polarization, and promoted M2 polarization of macrophages to reduce inflammation, thereby protecting skeletal muscle cells and indirectly promoting vascularization. Our results indicate that these bioceramic/alginate composite bioactive hydrogels are effective biomaterials for treating hindlimb ischemia and suggest that biomaterial-based approaches may have remarkable potential in treating ischemic diseases.

The role of the ERK signaling pathway in promoting angiogenesis for treating ischemic diseases.

The main treatment strategy for ischemic diseases caused by conditions such as poor blood vessel formation or abnormal blood vessels involves repairing vascular damage and encouraging angiogenesis. One of the mitogen-activated protein kinase (MAPK) signaling pathways, the extracellular signal-regulated kinase (ERK) pathway, is followed by a tertiary enzymatic cascade of MAPKs that promotes angiogenesis, cell growth, and proliferation through a phosphorylation response. The mechanism by which ERK alleviates the ischemic state is not fully understood. Significant evidence suggests that the ERK signaling pathway plays a critical role in the occurrence and development of ischemic diseases. This review briefly describes the mechanisms underlying ERK-mediated angiogenesis in the treatment of ischemic diseases. Studies have shown that many drugs treat ischemic diseases by regulating the ERK signaling pathway to promote angiogenesis. The prospect of regulating the ERK signaling pathway in ischemic disorders is promising, and the development of drugs that specifically act on the ERK pathway may be a key target for promoting angiogenesis in the treatment of ischemic diseases.

The role of exercise-induced myokines in promoting angiogenesis.

Ischemic diseases are a major cause of mortality or disability in the clinic. Surgical or medical treatment often has poor effect on patients with tissue and organ ischemia caused by diffuse stenoses. Promoting angiogenesis is undoubtedly an effective method to improve perfusion in ischemic tissues and organs. Although many animal or clinical studies tried to use stem cell transplantation, gene therapy, or cytokines to promote angiogenesis, these methods could not be widely applied in the clinic due to their inconsistent experimental results. However, exercise rehabilitation has been written into many authoritative guidelines in the treatment of ischemic diseases. The function of exercise in promoting angiogenesis relies on the regulation of blood glucose and lipids, as well as cytokines that secreted by skeletal muscle, which are termed as myokines, during exercise. Myokines, such as interleukin-6 (IL-6), chemokine ligand (CXCL) family proteins, irisin, follistatin-like protein 1 (FSTL1), and insulin-like growth factor-1 (IGF-1), have been found to be closely related to the expression and function of angiogenesis-related factors and angiogenesis in both animal and clinical experiments, suggesting that myokines may become a new molecular target to promote angiogenesis and treat ischemic diseases. The aim of this review is to show current research progress regarding the mechanism how exercise and exercise-induced myokines promote angiogenesis. In addition, the limitation and prospect of researches on the roles of exercise-induced myokines in angiogenesis are also discussed. We hope this review could provide theoretical basis for the future mechanism studies and the development of new strategies for treating ischemic diseases.

Therapeutic potential and molecular mechanisms of salidroside in ischemic diseases.

Rhodiola is an ancient wild plant that grows in rock areas in high-altitude mountains with a widespread habitat in Asia, Europe, and America. From empirical belief to research studies, Rhodiola has undergone a long history of discovery, and has been used as traditional medicine in many countries and regions for treating high-altitude sickness, anoxia, resisting stress or fatigue, and for promoting longevity. Salidroside, a phenylpropanoid glycoside, is the main active component found in all species of Rhodiola. Salidroside could enhance cell survival and angiogenesis while suppressing oxidative stress and inflammation, and thereby has been considered a potential compound for treating ischemia and ischemic injury. In this article, we highlight the recent advances in salidroside in treating ischemic diseases, such as cerebral ischemia, ischemic heart disease, liver ischemia, ischemic acute kidney injury and lower limb ischemia. Furthermore, we also discuss the pharmacological functions and underlying molecular mechanisms. To our knowledge, this review is the first one that covers the protective effects of salidroside on different ischemia-related disease.

Targeted delivery of nanomedicines for promoting vascular regeneration in ischemic diseases.

Ischemic diseases, the leading cause of disability and death, are caused by the restriction or blockage of blood flow in specific tissues, including ischemic cardiac, ischemic cerebrovascular and ischemic peripheral vascular diseases. The regeneration of functional vasculature network in ischemic tissues is essential for treatment of ischemic diseases. Direct delivery of pro-angiogenesis factors, such as VEGF, has demonstrated the effectiveness in ischemic disease therapy but suffering from several obstacles, such as low delivery efficacy in disease sites and uncontrolled modulation. In this review, we summarize the molecular mechanisms of inducing vascular regeneration, providing the guidance for designing the desired nanomedicines. We also introduce the delivery of various nanomedicines to ischemic tissues by passive or active targeting manner. To achieve the efficient delivery of nanomedicines in various ischemic diseases, we highlight targeted delivery of nanomedicines and controllable modulation of disease microenvironment using nanomedicines.

An Update on the Potential Application of Herbal Medicine in Promoting Angiogenesis.

Angiogenesis, the formation of new capillaries from pre-existing vascular networks, plays an important role in many physiological and pathological processes. The use of pro-angiogenic agents has been proposed as an attractive approach for promoting wound healing and treating vascular insufficiency-related problems, such as ischemic heart disease and stroke, which are the leading causes of death worldwide. Traditional herbal medicine has a long history; however, there is still a need for more in-depth studies and evidence-based confirmation from controlled and validated trials. Many in vitro and in vivo studies have reported that herbal medicines and their bioactive ingredients exert pro-angiogenic activity. The most frequently studied pro-angiogenic phytochemicals include ginsenosides from Panax notoginseng, astragalosides and calycosin from Radix Astragali, salvianolic acid B from Salvia miltiorrhiza, paeoniflorin from Radix Paeoniae, ilexsaponin A1 from Ilex pubescens, ferulic acid from Angelica sinensis, and puerarin from Radix puerariae. This review summarizes the progress in research on these phytochemicals, particularly those related to pro-angiogenic mechanisms and applications in ischemic diseases, tissue repair, and wound healing. In addition, an outline of their limitations and challenges during drug development is presented.