Role of angiogenesis and angiogenic factors in acute and chronic wound healing

Abstract

Angiogenesis plays a crucial role in wound healing by forming new blood vessels from preexisting vessels by invading the wound clot and organizing into a microvascular network throughout the granulation tissue. This dynamic process is highly regulated by signals from both serum and the surrounding extracellular matrix environment. Vascular endothelial growth factor, angiopoietin, fibroblast growth factor and transforming growth factor-beta are among the potent angiogenic cytokines in wound angiogenesis. Specific endothelial cell ECM receptors are critical for morphogenetic changes in blood vessels during wound repair. In particular integrin (αvβ3) receptors for fibrin and fibronectin, appear to be required for wound angiogenesis: αvβ3 is focally expressed at the tips of angiogenic capillary sprouts invading the wound clot, and any functional inhibitors of αvβ3 such as monoclonal antibodies, cyclic RGD peptide antagonists, and peptidomimetics rapidly inhibit granulation tissue formation. In spite of clear knowledge about influence of many angiogenic factors on wound healing, little progress has been made in defining the source of these factors, the regulatory events involved in wound angiogenesis and in the clinical use of angiogenic stimulants to promote repair.

Wound healing: cellular mechanisms and pathological outcomes

“…Angiogenesis is triggered by hypoxia, which in turn drives the expression of hypoxia-inducible factors (HIFs) and cyclooxygenase 2, and subsequent release of VEGF and other factors [69]. In response to these changes, microvascular endothelial cells proliferate and migrate into the wound bed, sprouting new vessels that fuse with others to develop stable, tubular networks [70]. VEGF prevents endothelial cell apoptosis by upregulating anti-apoptotic proteins such as BCL-2 [71], while the fibrin matrix promotes angiogenesis by triggering phenotypic changes in endothelial cells to stimulate their migration [72].…”

Instructive microenvironments in skin wound healing: Biomaterials as signal releasing platforms

“…Neovascularization involves the growth of new capillaries through angiogenesis in the injured site and, despite having a principal role in the proliferation stage, it is actually initiated immediately after tissue injury [28]. Angiogenesis is the growth of new vasculature from already existing blood vessels that can provide enough nutrients, oxygen and immune cells, and remove residues from the wound bed, which is indispensable for successful recovery [29] and maintenance of the tissue [20].…”

Identifying and treating foot ulcers in patients with diabetes: saving feet, legs and lives

“…Impaired neovascularisation and excess of MMPs are two major factors impeding the healing of chronic wounds, especially the ones encountered with vascular insufficiency. 128,129 Compounds have been shown to modulate MMP levels 130 and have effects on other cellular molecules, including growth factors and neovascularisation (sucrose octasulfate) 132 and other proteases and cytokines (collagen ORC). 133 Modulation of these signals has been shown to improve wound closure of DFUs, [134][135][136] demonstrating the potential of these healing enhancers.…”