Neuropilin Regulation of Angiogenesis, Arteriogenesis, and Vascular Permeability

Alice Plein,Alessandro Fantin,Christiana Ruhrberg

doi:10.1111/micc.12124

Alice Plein, Alessandro Fantin + Show 1 more

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https://doi.org/10.1111/micc.12124

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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.

Highlights

The cardiovascular system forms during embryonic development to supply growing organs with oxygen and nutrients via a hierarchical blood vessel network, with blood flow generated by the pumping heart
To directly evaluate the importance of VEGF binding to NRP1 for angiogenesis in vivo, we recently examined Nrp1Y297A/Y297A mice expressing NRP1 with a point mutation in the VEGF binding pocket [20], as the mutated residue was previously shown to be important for high affinity VEGF binding by NRP1 [40,43]
The most widely accepted model of NRP1 function in angiogenesis postulates that it forms a VEGF165-dependent complex with VEGFR2 to enhance the activation of a wide variety of intracellular signal transduction pathways, including those that involve (ERK) 1 and 2 (MAPK1 and MAPK3), the serine/threonine protein kinase RAC-alpha serine/threonine-protein kinase (AKT1), the avian sarcoma viral oncogene homolog proto-oncogene tyrosine-protein kinase Src (SRC), p38 mitogen-activated protein kinase (MAPK) (MAPK14) and the P130 CRK-associated substrate (CAS), known as breast cancer anti-estrogen resistance 1 (BCAR1) (Figure 1A) [1,5,19,46,51,89]

Summary

Introduction

The cardiovascular system forms during embryonic development to supply growing organs with oxygen and nutrients via a hierarchical blood vessel network, with blood flow generated by the pumping heart. Using Cre-LoxP technology to create cell type-specific NRP1 mutants in the hindbrain angiogenesis model, we recently examined the dependence of vascular development on endothelial versus nonendothelial NRP1.

Results

Conclusion