Figure 5. Molecular mechanisms of lumen morphogenesis.

a | Prior to lumen morphogenesis, blood vessels consist of coalesced cords of endothelial cells (ECs) that lack apicobasal polarity. β1 integrin–matrix interactions and RAS interacting protein 1 (RASIP1) establish EC apicobasal polarity in a partitioning defective 3 (PAR3)-mediated manner to promote the lateral redistribution of junctional components from the apical surface to the periphery of EC–EC contacts. b | Once EC apicobasal polarity is established, lumen formation is triggered, at least in part, by vascular endothelial cadherin (VE-cadherin)-mediated redistribution of CD34 and podocalyxin (PODXL) to the apical surface.β1 integrin may also promote the redistribution of PODXL to EC apical membranes. Subsequently, protein kinase C (PKC)-mediated phosphorylation and redistribution of moesin to PODXL-enriched apical EC membranes promotes the deposition of filamentous actin (F-actin). Furthermore, PODXL may initiate lumen formation by inducing the electrostatic repulsion of EC–EC apical surfaces. c | Lumenal expansion proceeds by a variety of mechanisms. For example, vascular endothelial growth factor receptor 2 (VEGFR2) signalling and activation of RHO-associated coiled-coil kinase (ROCK) may promote the association of non-muscle myosin II with apical F-actin to drive actomyosin-mediated cell shape changes. By contrast, RASIP1 may repress actomyosin contractility to fine-tune this response. Alternatively, or more likely in addition, directed exocytic vacuole trafficking and fusion of these vacuoles with the apical surface may also drive lumen expansion.

ZO1, zonula occludens 1; CLDN5, claudin 5.