Integrin β1 controls VE-cadherin localization and blood vessel stability

Abstract

Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin b1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that b1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin b1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin b1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

Endothelial basement membrane laminin 511 is essential for shear stress response

“…Similarly, inhibition of RhoA signalling, which has been implicated in both VE‐cadherin junctional localization and can also occur downstream of laminin–β1 integrin‐mediated interactions (Yamamoto et al , 2015), significantly reduced cell–cell adhesion strengths (Fig 5D). Taken together, the data suggest that the enhanced VE‐cadherin‐mediated cell–cell adhesion requires laminin 511 engagement with β1‐integrin but that laminin 511 may also act as a signalling molecule independent of its strong adhesive effects.…”

“…Cell–cell adhesion can be controlled by the complexity of junctional complexes or by the proportion of VE‐cadherin molecules located at junctions versus those recycling (Yamamoto et al , 2015). HUAEC cells were therefore plated at confluent densities on laminin 511, laminin 411 or laminin 111, and the VE‐cadherin recycling rate was measured with an antibody‐feeding assay (Yamamoto et al , 2015).…”

“…HUAEC cells were therefore plated at confluent densities on laminin 511, laminin 411 or laminin 111, and the VE‐cadherin recycling rate was measured with an antibody‐feeding assay (Yamamoto et al , 2015). Cells plated on laminin 511 showed lower proportions of vesicles containing internalized VE‐cadherin after 30 min of antibody feeding compared to cells plated on laminin 411 or laminin 111 (Fig 6A and B).…”

“…The maintenance and stability of cell–cell junctions is regulated by the balance of cell–cell adhesion and cellular contractility (Liu et al , 2010; Yamamoto et al , 2015). We therefore compared the level of phosphorylated myosin light chain II (pMLC II) in WT, Tek‐Cre::Lama5 −/− and Lama4 −/− mesenteric resistance arteries as a measure of actomyosin contractility (van Nieuw Amerongen et al , 2007; Abraham et al , 2009).…”

“…Recent data have shown enhanced displacement of VE‐cadherin from junctions to internal vesicles in a β1‐integrin‐dependent manner during angiogenic events in the mouse retina (Yamamoto et al , 2015). As β1‐integrins bind mainly ECM ligands, this suggests that the endothelial ECM may also affect junctional tightness.…”