Abstract
ABSTRACTEndothelial cell adhesion is implicated in blood vessel sprout formation, yet how adhesion controls angiogenesis, and whether it occurs via rapid remodeling of adherens junctions or focal adhesion assembly, or both, remains poorly understood. Furthermore, how endothelial cell adhesion is controlled in particular tissues and under different conditions remains unexplored. Here, we have identified an unexpected role for spatiotemporal c-Src activity in sprouting angiogenesis in the retina, which is in contrast to the dominant focus on the role of c-Src in the maintenance of vascular integrity. Thus, mice specifically deficient in endothelial c-Src displayed significantly reduced blood vessel sprouting and loss in actin-rich filopodial protrusions at the vascular front of the developing retina. In contrast to what has been observed during vascular leakage, endothelial cell-cell adhesion was unaffected by loss of c-Src. Instead, decreased angiogenic sprouting was due to loss of focal adhesion assembly and cell-matrix adhesion, resulting in loss of sprout stability. These results demonstrate that c-Src signaling at specified endothelial cell membrane compartments (adherens junctions or focal adhesions) control vascular processes in a tissue- and context-dependent manner.
Highlights
Blood vessels form complex branched networks comprising arteries, capillaries and veins that supply oxygen and nutrients to all body tissues
Expression of other Src family kinases (SFKs), Yes and Fyn, decreased upon loss of c-Src, the effect was significant only for Fyn (Fig. S3A-C). These results suggest that compensation by overexpression of other SFKs did not occur as a consequence of temporal endothelial c-Src deficiency
We show that c-Src is important for postnatal vascular development in the retina and trachea, by regulating endothelial cell-matrix adhesion, and is crucial for the outward growth and stabilization of new vessels during sprouting angiogenesis
Summary
Blood vessels form complex branched networks comprising arteries, capillaries and veins that supply oxygen and nutrients to all body tissues. A common denominator for these processes is hypoxia, which drives expression of vascular endothelial growth. Received 9 October 2019; Accepted 19 February 2020 factors (VEGFs), acting to initiate sprouting through binding and activation of VEGF receptors (VEGFRs). Signaling downstream of these ligand/receptor complexes is essential for vascular morphogenesis, as they control processes such as endothelial cell (EC) identity, migration, proliferation and vessel permeability (Simons et al, 2016). A greater understanding of the exquisite specificity of downstream signaling required for angiogenesis is becoming appreciated, in order to precisely target specific vascular processes in disease
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