Research ArticleAngiogenesis

The endothelial adaptor molecule TSAd is required for VEGF-induced angiogenic sprouting through junctional c-Src activation

Sci. Signal.  19 Jul 2016:
Vol. 9, Issue 437, pp. ra72
DOI: 10.1126/scisignal.aad9256

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Disconnecting endothelial cells for new blood vessels

The endothelial cells lining blood vessels are linked together by adherens junctions, where VE-cadherin protein complexes must come apart so that endothelial cells can migrate and proliferate to form new blood vessels. This process is triggered by activation of the receptor VEGFR2, which stimulates the kinase c-Src. Gordon et al. showed that the adaptor protein TSAd linked these two signaling molecules in the developing trachea. TSAd recruited active c-Src to adherens junctions, which resulted in the breakdown of VE-cadherin complexes and enabled the rearrangement of endothelial cells to form a new blood vessel sprout. Because TSAd was required for blood vessel formation in developing trachea, but not in the developing retina, TSAd could be targeted to prevent abnormal vascular growth in a tissue-specific manner.

Abstract

Activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by VEGF binding is critical for vascular morphogenesis. In addition, VEGF disrupts the endothelial barrier by triggering the phosphorylation and turnover of the junctional molecule VE-cadherin, a process mediated by the VEGFR2 downstream effectors T cell–specific adaptor (TSAd) and the tyrosine kinase c-Src. We investigated whether the VEGFR2-TSAd–c-Src pathway was required for angiogenic sprouting. Indeed, Tsad-deficient embryoid bodies failed to sprout in response to VEGF. Tsad-deficient mice displayed impaired angiogenesis specifically during tracheal vessel development, but not during retinal vasculogenesis, and in VEGF-loaded Matrigel plugs, but not in those loaded with FGF. The SH2 and proline-rich domains of TSAd bridged VEGFR2 and c-Src, and this bridging was critical for the localization of activated c-Src to endothelial junctions and elongation of the growing sprout, but not for selection of the tip cell. These results revealed that vascular sprouting and permeability are both controlled through the VEGFR2-TSAd–c-Src signaling pathway in a subset of tissues, which may be useful in developing strategies to control tissue-specific pathological angiogenesis.

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