Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function

Abstract

The motility and morphogenesis of endothelial cells is controlled by spatio-temporally regulated activation of integrin adhesion receptors, and integrin activation is stimulated by major determinants of vascular remodelling. In order for endothelial cells to be responsive to changes in activator gradients, the adhesiveness of these cells to the extracellular matrix must be dynamic, and negative regulators of integrins could be required. Here we show that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulates integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonize integrin activation. Misexpression of dominant negative SEMA3 receptors in chick embryo endothelial cells locks integrins in an active conformation, and severely impairs vascular remodelling. Sema3a null mice show vascular defects as well. Thus during angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function.

The brain within the tumor: new roles for axon guidance molecules in cancers

“…Accordingly, Sema3A seems to exert a permissive role on angiogenesis by inhibiting integrins-mediated adhesion of endothelial cells allowing their deadhesion. 50 The analysis of neuropilin-1 knockout mice has confirmed that neuropilin-1/ VEGF interaction is required for normal development of the vasculature. 51 A soluble neuropilin-1 isoform was identified and found to have robust antitumor activity.…”

“…47,48 Interestingly, Sema3A binding to neuropilin-1 blocks the migration of endothelial cells. 49 However, several class 3 semaphorins, including Sema3A are also expressed by endothelial cells 50 and could have an autocrine action. Accordingly, Sema3A seems to exert a permissive role on angiogenesis by inhibiting integrins-mediated adhesion of endothelial cells allowing their deadhesion.…”

Regulation of immune cell responses by semaphorins and their receptors

“…They were initially identified as repulsive axon guidance molecules that were required to direct neuronal axons to their appropriate targets. 9 More than 20 types of semaphorins have been identified, 10 and they have diverse functions in many physiological process, 11 including cardiogenesis, 12,13 angiogenesis, 14,15 vasculogenesis, 16 tumor metastasis, [17][18][19] osteoclastogenesis 20 and immune regulation. 21,22 In this review, we focus on two functional aspects of semaphorins, their roles in immune cell-cell interactions and immune cell trafficking.…”

Poxvirus semaphorin A39R inhibits phagocytosis by dendritic cells and neutrophils

“…Previous studies have shown that in neurons or cell lines, plexin engagement by semaphorins induces rearrangement of the actin cytoskeleton and inhibits integrinmediated cell adhesion, which leads to cellular retraction [13,14]. Although semaphorins and plexins are predominantly expressed in the nervous system, they can also be found in other tissues such as the vascular system [15] or the immune system [16]. In particular, Plexin C1 is expressed on DC and neutrophils (Walzer et al, in press).…”