A mechanosensitive transcriptional mechanism that controls angiogenesis

Abstract

Angiogenesis is controlled by physical interactions between cells and extracellular matrix as well as soluble angiogenic factors, such as VEGF. However, the mechanism by which mechanical signals integrate with other microenvironmental cues to regulate neovascularization remains unknown. Here we show that the Rho inhibitor, p190RhoGAP, controls capillary network formation in vitro and retinal angiogenesis in vivo by modulating the balance of activities between two antagonistic transcription factors – TFII-I and GATA2 – that govern gene expression of the VEGF receptor, VEGFR2. Moreover, this novel angiogenesis signaling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. This is the first known functional cross-antagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.

Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments

“…Importantly, this novel angiogenesis signalling pathway is sensitive to ECM elasticity as well as VEGF (Figure 7c). [138] This work suggested that an appropriate level of ECM stiffness might be required for optimal VEGFR2 expression and vascular development in vitro and in vivo. More recently, Picart and colleagues investigated mechanisms by which BMP-2 presented from surfaces is internalized by cells, and found this process to be also dependent on the stiffness of the substrate from which the GF was presented, with higher internalisation rates on soft substrates.…”

Concise Review: Mechanotransduction via p190RhoGAP Regulates a Switch Between Cardiomyogenic and Endothelial Lineages in Adult Cardiac Progenitors

“…Previous studies have implicated a small GTPase, RhoA, as an important molecular player in regulation of cell responses to mechanical cues, as well as in controlling cell morphology, and interaction with other cells [6,32]. Cardiac tissue generation and morphogenesis involve all the above processes.…”

“…In other words, the mechanical properties of the surrounding environment, such as matrix elasticity, can not only permit or enhance certain predefined differentiation outcomes but also determine which lineage is adopted by multipotent stem or precursor cells [8]. In addition, mechanical cues have long been known to play a role in tissue morphogenesis in various settings, including luminal morphogenesis of differentiated endothelial cells [6], striated morphogenesis of muscle cells [9], and polarized separation of basal lamina and apical membrane in epithelial cells [12]. Therefore, it is instructive to explore whether the seemingly independent phenomena involved in tissue repair: proliferation of stem cells, differentiation into somatic cells, and tissue morphogenesis might be regulated directly by the extracellular mechanical cues.…”

“…In addition, p190RhoGAP was necessary for the lacunae formation by the differentiating endothelial cells. p190Rho-GAP has been previously implicated to be important in the rigidity-induced 3D luminal network formation, and VEGFR2 expression in mature endothelial cells [6]. 3D cell clusters inevitably require cell-cell contact that is known to downregulate RhoA via p190RhoGAP-B [30].…”

“…Extensive knowledge has been accumulated regarding mechanisms underlying stem cell proliferation [3], differentiation [4,5], and morphogenesis [6,7]. Many extracellular cues, in particular growth factors and mechanical cues, are known to strongly influence the above phenomena, when analyzed separately both in vitro, and in vivo [8].…”