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Received for publication June 2, 2006.
Revised August 25, 2006.
Accepted for publication August 28, 2006.
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.
Key words:
MAPK, angiogenesis, cGMP, endothelial cells, migration, soluble guanylyl cyclase
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