PKG-I inhibition attenuates vascular endothelial growth factor-stimulated angiogenesis

Vasiliki Koika, Zongmin Zhou, Ioannis Vasileiadis, Charis Roussos, Federica Finetti, Martina Monti, Lucia Morbidelli, Andreas Papapetropoulos

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Vascular endothelial growth factor (VEGF) stimulates nitric oxide (NO) production, which mediates many of its angiogenic actions. However, the angiogenic pathways that operate downstream of NO following VEGF treatment are not well characterized. Herein, we used DT-2 and DT-3, two highly selective cGMP-dependent protein kinase I peptide inhibitors to determine the contribution of PKG-I in VEGF-stimulated angiogenesis. Incubation of chicken chorioallantoic membranes (CAM) with PKG-I peptide inhibitors decreased vascular length in a dose-dependent manner, with DT-3 being more effective than DT-2. Moreover, inhibition of PKG-I with DT-3 abolished the angiogenic response elicited by VEGF in the rabbit eye cornea. PKG-I inhibition also blocked VEGF-stimulated vascular leakage. In vitro, treatment of cells with VEGF stimulated phosphorylation of the PKG substrate VASP through VEGFR2 activation; the VEGF-stimulated VASP phosphorylation was reduced by DT-2. Pre-treatment of cells with DT-2 or DT-3 inhibited VEGF-stimulated mitogen-activated protein kinase cascades (ERK1/2 and p38), growth, migration and sprouting of endothelial cells. The above observations taken together identify PKG-I as a downstream effector of VEGFR2 in EC and provide a rational basis for the use of PKG-I inhibitors in disease states characterized by excessive neovascularization.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalVascular Pharmacology
Volume53
Issue number5-6
DOIs
StatePublished - Nov 1 2010
Externally publishedYes

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Keywords

  • Angiogenesis
  • CGMP
  • PKG
  • Vascular endothelium
  • VEGF

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

Koika, V., Zhou, Z., Vasileiadis, I., Roussos, C., Finetti, F., Monti, M., Morbidelli, L., & Papapetropoulos, A. (2010). PKG-I inhibition attenuates vascular endothelial growth factor-stimulated angiogenesis. Vascular Pharmacology, 53(5-6), 215-222. https://doi.org/10.1016/j.vph.2010.08.004