Capillaries consist of a single layer of squamous endothelium sitting on a basement membrane, measuring around 5-10 micrometers in diameter , . The endothelial cells perform the function of regulating permeability and subsequently the exchange of oxygen, nutrients, carbon dioxide and waste products . Additionally, they are the only cell to directly contact blood under physiological conditions. Endothelial cells functions include but are not limited to regulating immune response, initiating growth of new blood vessels and regulation of blood clotting .
Neovasculature is initially formed during embryonic development and is maintained throughout life in response to various stimulating factors such as growth or injury , . Neovascularization can occur via two distinctly different processes, vasculogenesis or angiogenesis , . Vasculogenesis is the process by which new vessels are formed de novo in early embryonic development , , , . The vascular lattice formed from vasculogenesis then forms the structural basis for angiogenesis , . Angiogenesis is the physiological process by which new blood vessels are formed from preexisting ones in a rigorously defined way , , . This process can occur via either proliferative invasive sprouting of the vascular network into the surrounding tissue or by intussusception, the remodeling of vessels by the division into two or more daughter vessels –.
Sprouting angiogenesis is of particular interest as it is generally initiated due to hypoxia in cells or upon wounding, leading to the release of pro-angiogenic mediators , –. Vascular-endothelial growth factor (VEGF) is the most prominent of these mediators . Upon secretion by damaged cells, macrophages or fibroblasts it diffuses into the surrounding tissue and triggers the ingrowth of new blood vessels , –. VEGF selectively acts upon endothelial cells situated in proximal blood vessels triggering a cascade of events , . Upon VEGF binding, endothelial cells convert from a quiescent state to an active phenotype characterized by a high proliferative and migratory ability . The endothelial cells release matrix metalloproteinases (MMPs) that act upon the basement membrane of the parent vessel releasing the endothelial cells into the extravascular space , , . The endothelial cells form sprouts and migrate via proliferation towards the hypoxic cells or wounds site, continuing to secrete proteolytic enzymes allowing movement through the extracellular matrix (ECM) , .
Fusing of two endothelial sprouts leads to the formation of a lumen and an immature blood vessel , . The final step being the maturation of the blood vessel via development of a basement membrane, allowing the supply of oxygen and repair of wounds sites . Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the vasculature , .
Fibroblasts play a key supporting role in angiogenesis, without which severely stunted blood vessel growth results , . They have a key role as synthesisers and modifiers of the ECM, in addition they secrete soluble angiogenic factors such as VEGF, inducing endothelial cells sprouting and vessel formation –.
Despite the focus on VEGF there are many other angiogenic mediators that have significant contributions to the process , , . Angiogenic mediators can have direct effects on endothelial cells as described with VEGF or indirect effects related to supporting angiogenesis , . These mediators include hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) which directly enhance motility and proliferation of endothelial cells , , , .
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