Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis

Abstract

The endothelial cells that compose the vascular system in the body display a wide range of mechanotransductive behaviors and responses to biomechanical stimuli, which act in concert to control overall blood vessel structure and function. Such mechanosensitive activities allow blood vessels to constrict, dilate, grow, or remodel as needed during development as well as normal physiological functions, and the same processes can be dysregulated in various disease states. Mechanotransduction represents cellular responses to mechanical forces, translating such factors into chemical or electrical signals which alter the activation of various cell signaling pathways. Understanding how biomechanical forces drive vascular growth in healthy and diseased tissues could create new therapeutic strategies that would either enhance or halt these processes to assist with treatments of different diseases. In the cardiovascular system, new blood vessel formation from preexisting vasculature, in a process known as angiogenesis, is driven by vascular endothelial growth factor (VEGF) binding to VEGF receptor 2 (VEGFR-2) which promotes blood vessel development. However, physical forces such as shear stress, matrix stiffness, and interstitial flow are also major drivers and effectors of angiogenesis, and new research suggests that mechanical forces may regulate VEGFR-2 phosphorylation. In fact, VEGFR-2 activation has been linked to known mechanobiological agents including ERK/MAPK, c-Src, Rho/ROCK, and YAP/TAZ. In vascular disease states, endothelial cells can be subjected to altered mechanical stimuli which affect the pathways that control angiogenesis. Both normalizing and arresting angiogenesis associated with tumor growth have been strategies for anti-cancer treatments. In the field of regenerative medicine, harnessing biomechanical regulation of angiogenesis could enhance vascularization strategies for treating a variety of cardiovascular diseases, including ischemia or permit development of novel tissue engineering scaffolds. This review will focus on the impact of VEGFR-2 mechanosignaling in endothelial cells (ECs) and its interaction with other mechanotransductive pathways, as well as presenting a discussion on the relationship between VEGFR-2 activation and biomechanical forces in the extracellular matrix (ECM) that can help treat diseases with dysfunctional vascular growth.

Impact of cyanidin 3-<i>O</i>-glucoside on rat micro-and systemic circulation, possibly thorough angiogenesis

“…The mechano-sensitivity of endothelial cells induces blood vessel constriction, dilation, growth, or remodeling, as needed during development and under normal physiological conditions. (15) Recently, it was suggested that impaired angiogenesis could contribute to increased peripheral resistance, which leads to increased blood pressure. (16,17) Essential hypertension is thought to be a consequence of structural and functional alterations in the growth of the microvascular network, due to abnormal regulation of angiogenesis.…”

The physiological mechanism and effect of resistance exercise on cognitive function in the elderly people

“…Importantly, BDNF produced after resistance exercise has direct or indirect interaction with IGF-1, that is, it can help the brain increase IGF-1, promote nerve growth and produce serum angiotensin and amino acid, and then stimulate more BDNF receptors to increase the connection between neurons. This neurobiochemical mechanism can act on such central nervous system regions as the forebrain, striatum, hippocampus, cerebral cortex, spetum neurons, cerebellum, and motor neurons ( 98 ). These brain structures are all related to cognitive processing.…”

Sprouting Angiogenesis in Human Pituitary Adenomas

“…We found that its expression in human pituitary tumors is approximately 2-fold that of normal pituitary tissue (FLT1 in Figure 1 ). VEGFR2 is expressed mostly in vascular endothelial cells ( 68 ). Both VEGFA and VEGFC bind to VEGFR2.…”

“…Both VEGFA and VEGFC bind to VEGFR2. VEGFR2 is the predominant receptor mediating VEGF-induced vascular angiogenesis ( 29 , 68 ). Consistent with this, we found that VEGFR2 expression is more than 8-fold higher in pituitary tumors than in normal pituitary tissue (KDR in Figure 3A ).…”