Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability

Abstract

The formation of the cardiovasculature, consisting of both the heart and blood vessels, is a critical step in embryonic development and relies on three processes termed vasculogenesis, angiogenesis, and vascular remodeling. The transmembrane protein NRP1 is an essential modulator of embryonic angiogenesis with additional roles in vessel remodeling and arteriogenesis. NRP1 also enhances arteriogenesis in adults to alleviate pathological tissue ischemia. However, in certain circumstances, vascular NRP1 signaling can be detrimental, as it may promote cancer by enhancing tumor angiogenesis or contribute to tissue edema by increasing vascular permeability. Understanding the mechanisms of NRP1 signaling is, therefore, of profound importance for the design of therapies aiming to control vascular functions. Previous work has shown that vascular NRP1 can variably serve as a receptor for two secreted glycoproteins, the VEGF-A and SEMA3A, but it also has a poorly understood role as an adhesion receptor. Here, we review current knowledge of NRP1 function during blood vessel growth and homeostasis, with special emphasis on the vascular roles of its multiple ligands and signaling partners.

Keywords: NRP1; SEMA3A; VEGF; VEGF-A; VEGFR2; angiogenesis; arteriogenesis; endothelial cells; neuropilin; vascular permeability.

Figure 1

NRP1-regulated signaling pathways in endothelial cells in vitro. (A) VEGF165 induces complex formation between NRP1 and VEGFR2 to enhance VEGFR2 signaling in endothelial cells in vitro. In particular, biochemical studies suggested possible roles for NRP1 in the VEGF-mediated induction of pathways involving the activation of ERK, AKT, SRC, P38 MAPK, and p130 CAS. (B) NRP1 regulates integrin-dependent fibronectin remodeling in primary arterial endothelial cells and tumor cells in a mechanism that depends on the NRP1 cytoplasmic domain, but is thought to be VEGFR2 independent.