Neuropilin-1 Regulates Vascular Endothelial Growth Factor–Mediated Endothelial Permeability

Author:

Becker Patrice M.1,Waltenberger Johannes1,Yachechko Robin1,Mirzapoiazova Tamara1,Sham James S.K.1,Lee Chun Geun1,Elias Jack A.1,Verin Alexander D.1

Affiliation:

1. From the Division of Pulmonary and Critical Care Medicine (P.M.B., R.Y., T.M., J.S.K.S., A.D.V.), Johns Hopkins University School of Medicine, Baltimore, Md; University Hospital Maastricht and Cardiovascular Research Institute Maastricht (CARIM) (J.W.), Maastricht, the Netherlands; and the Division of Pulmonary and Critical Care Medicine (C.G.L., J.A.E.), Yale University School of Medicine, New Haven, Conn.

Abstract

Neuropilin-1 (Npn-1) is a cell surface receptor that binds vascular endothelial growth factor (VEGF), a potent mediator of endothelial permeability, chemotaxis, and proliferation. In vitro, Npn-1 can complex with VEGF receptor-2 (VEGFR2) to enhance VEGFR2-mediated endothelial cell chemotaxis and proliferation. To determine the role of Npn-1/VEGFR2 complexes in VEGF-induced endothelial barrier dysfunction, endothelial cells were stably transfected with Npn1 or VEGFR2 alone (PAE/Npn and PAE/KDR, respectively), or VEGFR2 and Npn-1 (PAE/KDR/Npn-1). Permeability, estimated by measurement of transendothelial electrical resistance (TER), of PAE/Npn and PAE/KDR cell lines was not altered by VEGF 165 . In contrast, TER of PAE/KDR/Npn-1 cells decreased in dose-dependent fashion following VEGF 165 (10 to 200 ng/mL). Activation of VEGFR2, and 2 downstream signaling intermediates (p38 and ERK1/2 MAPK) involved in VEGF-mediated permeability, also increased in PAE/KDR/Npn-1. Consistent with these data, inhibition of Npn-1, but not VEGFR2, attenuated VEGF 165 -mediated permeability of human pulmonary artery endothelial cells (HPAE), and VEGF 121 (which cannot ligate Npn-1) did not alter TER of HPAE. Npn-1 inhibition also attenuated both VEGF 165 -mediated pulmonary vascular leak and activation of VEGFR2, p38, and ERK1/2 MAPK, in inducible lung-specific VEGF transgenic mice. These data support a critical role for Npn-1 in regulating endothelial barrier dysfunction in response to VEGF and suggest that activation of distinct receptor complexes may determine specificity of cellular response to VEGF.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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