Therapeutic angiogenesis and tissue revascularization in ischemic vascular disease

Abstract

Ischemic vascular disease is a major healthcare problem. The keys to treatment lie in vascular regeneration and restoration of perfusion. However, current treatments cannot satisfy the need for vascular regeneration to restore blood circulation. As biomedical research has evolved rapidly, a variety of potential alternative therapeutics has been explored widely, such as growth factor-based therapy, cell-based therapy, and material-based therapy including nanomedicine and biomaterials. This review will comprehensively describe the main pathogenesis of vascular injury in ischemic vascular disease, the therapeutic function of the above three treatment strategies, the corresponding potential challenges, and future research directions.

Keywords: Biological therapy; Ischemic vascular disease; Therapeutic angiogenesis; Tissue revascularization.

Fig. 1

The main therapeutic mechanisms of growth factors in ischemic vascular disease. The mechanism of HGF is mediated through its unique tyrosine kinase receptor (c-Met), which could drive intracellular signaling pathways (including the RAS‐MAPK, PI3K‐protein kinase B, and mTOR pathways). FGF regulates biological functions including cell proliferation, survival, migration, and differentiation by binding and activating FGF receptors via the RAS/MAPK pathway. PDGF gets involved in IVD through the PI3K pathway, the RAS pathway, and the PLC pathway. The induction of endothelial cells called tip, stem, and finger osteoblasts through interactions between VEGF and its receptor (VEGFR1-3) and between Notch and Delta-like nick ligands is essential for the regulation of angiogenesis. c-Met: cellular-mesenchymal epithelial transition factor; DAG: diacylglycerol; FGF: fibroblast growth factor; FGFR: fibroblast growth factor receptor; GEF: GMP exchange factor; HGF: hepatocyte growth factor; IP₃: inositol triphosphate; IVD: ischemic vascular disease; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; PLC: phospholipase C; PKC: protein kinase C; PI3K: phosphatidylinositide 3-kinases; RAS: rat sarcoma; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor. The figure was created by Figdraw (https://www.figdraw.com/)

Fig. 2

The main therapeutic mechanism of stem cells in ischemic vascular disease. Mesenchymal stem cells, endothelial progenitor cells, and induced pluripotent stem cells are the main stem cells used to treat ischemic vascular disease. These cells mainly exert their angiogenesis, anti-apoptosis, anti-inflammation, pro-proliferation, anti-fibrosis, and neurogenesis function through differentiation, paracrine effects, and immunoregulation. The figure was constructed with BioRender (https://biorender.com/)

Fig. 3

Three potential alternative therapeutics in ischemic vascular disease: growth factor-based therapy, cell-based therapy, and material-based therapy including nanomedicine and biomaterials. HGF: hepatocyte growth factor; FGF: fibroblast growth factor; PDGF: platelet-derived growth factor; VEGF: vascular endothelial growth factor; MSCs: mesenchymal stem cells; EPCs: endothelial progenitor cells; iPSCs: induced pluripotent stem cells. The figure was constructed with BioRender (https://biorender.com)