Publications [#80088] of Christopher D. Kontos

Papers Published

1. B Bussolati, C Dunk, M Grohman, CD Kontos, J Mason, A Ahmed, Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide., The American journal of pathology, United States, vol. 159 no. 3 (September, 2001), pp. 993-1008, ISSN 0002-9440
   (last updated on 2007/12/01)

   Abstract:
   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.

   Keywords:
   Cell Division • Cells, Cultured • Endothelial Growth Factors • Endothelium, Vascular • Humans • Lymphokines • Neovascularization, Physiologic • Nitric Oxide • Nitric Oxide Donors • Nitric Oxide Synthase • Nitric Oxide Synthase Type III • Nitroso Compounds • Penicillamine • Protein Isoforms • Proto-Oncogene Proteins • Receptor Protein-Tyrosine Kinases • Receptors, Growth Factor • Receptors, Vascular Endothelial Growth Factor • Transfection • Vascular Endothelial Growth Factor A • Vascular Endothelial Growth Factor Receptor-1 • Vascular Endothelial Growth Factors • analogs & derivatives • antagonists & inhibitors • cytology • drug effects • genetics • immunology • metabolism • pharmacology • physiology • physiology*