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(Circulation Research. 2005;96:1257.)
© 2005 American Heart Association, Inc.

Molecular Medicine

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

Patrice M. Becker, Johannes Waltenberger, Robin Yachechko, Tamara Mirzapoiazova, James S.K. Sham, Chun Geun Lee, Jack A. Elias, Alexander D. Verin

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.

Correspondence to Dr Patrice M. Becker, Johns Hopkins Asthma and Allergy Center, Room 4B74, 5501 Hopkins Bayview Cir, Baltimore, MD 21224. E-mail pbecker1{at}jhmi.edu

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 VEGF₁₆₅. In contrast, TER of PAE/KDR/Npn-1 cells decreased in dose-dependent fashion following VEGF₁₆₅ (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 VEGF₁₆₅-mediated permeability of human pulmonary artery endothelial cells (HPAE), and VEGF₁₂₁ (which cannot ligate Npn-1) did not alter TER of HPAE. Npn-1 inhibition also attenuated both VEGF₁₆₅-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.

Key Words: vascular endothelial growth factor receptor-2 • transendothelial electrical resistance • chemotaxis • mitogen-activated protein kinase • acute lung injury

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