Vascular remodelling depends on interactions between endothelial cells (ECs) and the extracellular matrix (ECM). Key to this interaction are focal adhesions (FAs), which anchor ECs to the ECM and facilitate signal transmission from the environment. This interaction is regulated by the kinase c-Src, as loss of c-Src in ECs attenuates FA signalling and, consequently, vessel sprouting. However, how elevated c-Src signalling impacts vessel growth is unclear. In this work (Essebier et al., 2024), Gordon and colleagues investigate the effect of c-Src hyperactivation on cell adhesion and vascular behaviour. The authors find that in 3D vascular models, expression of a constitutively active c-Src (c-Src-CA) in ECs induces a ballooning phenotype, with vessels lacking angiogenic sprouts and with a discontinuous cellular lining. In addition, c-Src-CA expression results in enlarged FAs, phosphorylation of the FA component paxillin and loss of cell–cell junction integrity due to phosphorylation and internalization of the junctional component VE-cadherin. Interestingly, the authors also observe increased matrix metalloproteinase (MMP) secretion, and thus ECM degradation, at enlarged FAs. Consistent with this, pharmacological MMP inhibition rescues the vascular ballooning induced by c-Src-CA. Together, this work uncovers how c-Src, by modulating FA turnover and MMP secretion, regulates endothelial dynamics, and highlights the importance of precise cell–matrix interactions in enabling functional angiogenesis.
