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

Research output: Contribution to journalArticle

94 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1257-1265
Number of pages9
JournalCirculation research
Volume96
Issue number12
DOIs
StatePublished - Jun 24 2005
Externally publishedYes

Keywords

  • Acute lung injury
  • Chemotaxis
  • Mitogen-activated protein kinase
  • Transendothelial electrical resistance
  • Vascular endothelial growth factor receptor-2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Becker, P. M., Waltenberger, J., Yachechko, R., Mirzapoiazova, T., Sham, J. S. K., Lee, C. G., Elias, J. A., & Verin, A. D. (2005). Neuropilin-1 regulates vascular endothelial growth factor-mediated endothelial permeability. Circulation research, 96(12), 1257-1265. https://doi.org/10.1161/01.RES.0000171756.13554.49