ZFIN ID: ZDB-PUB-060906-13
Soluble guanylyl cyclase activation promotes angiogenesis
Pyriochou, A., Beis, D., Koika, V., Polytarchou, C., Papadimitriou, E., Zhou, Z., and Papapetropoulos, A.
Date: 2006
Source: The Journal of pharmacology and experimental therapeutics   319(2): 663-671 (Journal)
Registered Authors: Beis, Dimitris
Keywords: MAPK, angiogenesis, cGMP, endothelial cells, migration, soluble guanylyl cyclase
MeSH Terms:
  • Animals
  • COS Cells
  • Cell Proliferation
  • Cells, Cultured
  • Chlorocebus aethiops
  • Endothelial Cells/physiology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases/physiology
  • Guanylate Cyclase/physiology*
  • Humans
  • Neovascularization, Physiologic*
  • Nitric Oxide/physiology
  • Phenotype
  • Pyrazoles/pharmacology
  • Pyridines/pharmacology
  • Vascular Endothelial Growth Factor A/pharmacology
PubMed: 16940434 Full text @ J. Pharmacol. Exp. Ther.
Soluble guanylyl cyclase (sGC) is a cGMP-generating enzyme, carrying a heme prosthetic group that functions as a nitric oxide (NO) sensor. sGC is present in most cells types, including the vascular endothelium, where its biological functions remain largely unexplored. Herein, we have investigated the role of sGC in angiogenesis and angiogenesis-related properties of endothelial cells (EC). Initially, we determined that sGC was present and enzymatically active in the chicken chorioallantoic membrane (CAM) during the days of maximal angiogenesis. In the CAM, inhibition of endogenous sGC inhibited neovascularization, while activation promoted neovessel formation. Using zebrafish as a model for vascular development, we did not detect any effect on vasculogenesis upon sGC blockade, but we did observe an abnormal angiogenic response involving the cranial and intersegmental vessels, as well as the posterior cardinal vein. In vitro, pharmacological activation of sGC, or adenovirus-mediated sGC gene transfer promoted EC proliferation and migration, while sGC inhibition blocked tube-like network formation. In addition, sGC inhibition blocked the migratory response to vascular EC growth factor. Cells infected with sGC-expressing adenoviruses exhibited increased ERK1/2 and p38 MAPK activation that was sensitive to sGC inhibition by ODQ, suggesting that these MAPKs are downstream effectors of sGC in EC. A functional role for p38 in cGMP-stimulated migration was demonstrated using SB203580; pharmacological inhibition of p38 attenuated BAY-412272- and sGC overexpression-induced EC mobilization. We conclude that sGC activation promotes the expression of angiogenesis-related properties by EC and that sGC might represent a novel target to modulate neo-vessel formation.