αvβ3 Integrin Limits the Contribution of Neuropilin-1 to Vascular Endothelial Growth Factor-induced Angiogenesis

Louise E. Reynolds,Marianne Baker,Kairbaan M. Hodivala-Dilke,Stephen D. Robinson,Rita Graça da Silva,Vassiliki Kostourou,Andrew R. Reynolds,John F. Marshall,Bernardo Tavora

doi:10.1074/jbc.m109.030700

Louise E. Reynolds, Marianne Baker

Open Access

https://doi.org/10.1074/jbc.m109.030700

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Abstract

Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that beta3 integrin can regulate negatively VEGFR2 expression. Here we show that beta3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of alphav beta3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when beta3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of beta3 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that alphav beta3 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that beta3 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2.

Highlights

Tumors, for example, become refractory to anti-Vascular endothelial growth factor (VEGF) therapies [3]
VEGF-induced Motility of ␤3-Null endothelial cell (EC) in Vitro Is Dependent on NRP1— Confident that we were studying an EC-specific process, we investigated the contributions made by VEGFR2, NRP1, and ␤3 integrin to VEGF-A164-mediated events in vitro
Enhanced VEGFR2-mediated Signaling in ␤3-Null Endothelial Cells Is NRP1-dependent—To understand better the molecular mechanisms underlying our results so far, we investigated the levels of VEGFR2 and NRP1 expressed by WT and ␤3-null primary lung ECs

Summary

Introduction

Tumors, for example, become refractory to anti-VEGF therapies [3]. This has led to the recent idea of simultaneously targeting convergent proangiogenic pathways. Recent data have shown that blockade of both ␣v␤3 integrin and VEGFR2 increases the efficacy of antiangiogenic therapy in vivo [9]. Our data suggest that the clinical efficacy of any therapeutic approach that targets these two interacting proteins is likely to be dependent on other molecules that affect VEGFR2 or ␣v␤3 integrin activity. VEGFR2 signaling is influenced by associations with NRP1 (neuropilin-1), a co-receptor for some VEGF isoforms [10, 11]. Both peptides and antibodies that block the binding of VEGF to NRP1 can enhance antiVEGF therapy and inhibit tumor growth [12,13,14]. We set out to determine what role NRP1 plays in ␤3 integrin-dependent, VEGF-induced angiogenesis

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