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.
Highlights
Angiogenesis, or the development of blood vessels from preexisting vasculature, is a pillar of normal development and growth; various disease states are associated with dysregulation of blood vessel growth
We will use biochemical signaling to refer to the binding of vascular endothelial growth factor (VEGF) to VEGF receptor 2 (VEGFR-2), while biomechanical signaling will refer to VEGFR-2 activation or downstream signaling induced by non-ligand binding cues
Mechanotransduction is the process by which mechanical signals from the extracellular matrix (ECM), nearby cells, or surrounding fluids interact with a cell and are subsequently processed into a biochemical signaling cascade of various proteins to regulate the cellular response to the mechanical cue
Summary
Angiogenesis, or the development of blood vessels from preexisting vasculature, is a pillar of normal development and growth; various disease states are associated with dysregulation of blood vessel growth. Much research has focused on either inhibiting or promoting angiogenic processes to treat diseases, but these therapeutic approaches have shown mixed results Perhaps some of these failures are due in part to the focus on biochemical regulation of angiogenesis while ignoring mechanical cues that could be controlling blood vessel development. In larger vessels of the arterial system, a pulsatile fluid pressure wave is experienced with every heartbeat [3] Together, these forces may alter endothelial cell behaviors in underappreciated manners that could affect the growth and development of new vasculature. In the tumor microenvironment (TME), matrix remodeling initiated by stromal and tumor cells increases matrix stiffness, usually through increased collagen deposition and organization This increases both compressive forces on the cells and vessels, forcing higher levels of interstitial flow as fluids are “squeezed” from the vessels and generating irregular shear stresses. Understanding how mechanotransduction by endothelial cells regulates angiogenesis will provide critical knowledge in how to promote or inhibit blood vessel growth in the dysregulated biomechanical environments of various disease states
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