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Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide.

Publication ,  Journal Article
Bussolati, B; Dunk, C; Grohman, M; Kontos, CD; Mason, J; Ahmed, A
Published in: Am J Pathol
September 2001

The known responses of vascular endothelial growth factor (VEGF) are mediated through VEGF receptor-2 (VEGFR-2/KDR) in endothelial cells. However, it is unknown whether VEGFR-1 (Flt-1) is an inert decoy or a signaling receptor for VEGF during physiological or pathological angiogenesis. Here we report that VEGF-stimulated nitric oxide (NO) release is inhibited by blockade of VEGFR-1 and that VEGFR-1 via NO negatively regulates of VEGFR-2-mediated proliferation and promotes formation of capillary networks in human umbilical vein endothelial cells (HUVECs). Inhibition of VEGFR-1 in a murine Matrigel angiogenesis assay induced large aneurysm-like structures. VEGF-induced capillary growth over 14 days was inhibited by anti-VEGFR-2-blocking antibody as determined by reduced tube length between capillary connections (P < 0.0001) in an in vitro angiogenesis assay. In contrast, loss of VEGFR-1 activity with a neutralizing anti-VEGFR-1 antibody resulted in an increase in the accumulation of endothelial cells (P < 0.0001) and a dramatic decrease in the number of capillary connections that were restored by the addition of NO donor. Porcine aortic endothelial (PAE) cells expressing human VEGFR-1 but not VEGFR-2 plated on growth factor-reduced Matrigel rearranged into tube-like structures that were prevented by anti-VEGFR-1 antibody or a cGMP inhibitor. VEGF stimulated NO release from VEGFR-1- but not VEGFR-2-transfected endothelial cells and placenta growth factor-1 stimulated NO release in HUVECs. Blockade of VEGFR-1 increased VEGF-mediated HUVEC proliferation that was inhibited by NO donors, and potentiated by NO synthase inhibitors. These data indicate that VEGFR-1 is a signaling receptor that promotes endothelial cell differentiation into vascular tubes, in part by limiting VEGFR-2-mediated endothelial cell proliferation via NO, which seems to be a molecular switch for endothelial cell differentiation.

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Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

September 2001

Volume

159

Issue

3

Start / End Page

993 / 1008

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor A
  • Transfection
  • Receptors, Vascular Endothelial Growth Factor
  • Receptors, Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Protein Isoforms
  • Penicillamine
 

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Bussolati, B., Dunk, C., Grohman, M., Kontos, C. D., Mason, J., & Ahmed, A. (2001). Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol, 159(3), 993–1008. https://doi.org/10.1016/S0002-9440(10)61775-0
Bussolati, B., C. Dunk, M. Grohman, C. D. Kontos, J. Mason, and A. Ahmed. “Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide.Am J Pathol 159, no. 3 (September 2001): 993–1008. https://doi.org/10.1016/S0002-9440(10)61775-0.
Bussolati B, Dunk C, Grohman M, Kontos CD, Mason J, Ahmed A. Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol. 2001 Sep;159(3):993–1008.
Bussolati, B., et al. “Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide.Am J Pathol, vol. 159, no. 3, Sept. 2001, pp. 993–1008. Pubmed, doi:10.1016/S0002-9440(10)61775-0.
Bussolati B, Dunk C, Grohman M, Kontos CD, Mason J, Ahmed A. Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol. 2001 Sep;159(3):993–1008.
Journal cover image

Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

September 2001

Volume

159

Issue

3

Start / End Page

993 / 1008

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor A
  • Transfection
  • Receptors, Vascular Endothelial Growth Factor
  • Receptors, Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Protein Isoforms
  • Penicillamine