Exp Mol Med.
2005 Dec;37(6):588-600.
Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells
- Affiliations
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- 1Vascular System Research Center, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea. ymkim@kangwon.ac.kr
- 2Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea.
- 3Department of Microbiology and Immunology, School of Medicine, Wonkwang University, Iksan 570-749, Korea.
- 4Department of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea.
Abstract
- Prostaglandin E2(PGE2), a major product of cyclooxygenase, has been implicated in modulating angiogenesis, vascular function, and inflammatory processes, but the underlying mechanism is not clearly elucidated. We here investigated the molecular mechanism by which PGE 2 regulates angiogenesis. Treatment of human umbilical vein endothelial cells (HUVEC) with PGE 2 increased angiogenesis. PGE 2 increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), eNOS activity, and nitric oxide (NO) production by the activation of cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K). Dibutyryl cAMP (DB-cAMP) mimicked the role of PGE 2 in angiogenesis and the signaling pathway, suggesting that cAMP is a down-stream mediator of PGE 2. Furthermore, PGE 2 increased endothelial cell sprouting from normal murine aortic segments, but not from eNOS-deficient ones, on Matrigel. The angiogenic effects of PGE 2 were inhibited by the inhibitors of PKA, PI3K, eNOS, and soluble guanylate cyclase, but not by phospholipase C inhibitor. These results clearly show that PGE 2 increased angiogenesis by activating the NO/cGMP signaling pathway through PKA/PI3K/Akt-dependent increase in eNOS activity.
MeSH Terms
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1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors
Animals
Aorta
Cell Movement/drug effects
Cell Proliferation/drug effects
Cyclic AMP/metabolism/pharmacology
Cyclic GMP/biosynthesis/*metabolism
Dinoprostone/*pharmacology
Endothelial Cells/*drug effects/metabolism
Enzyme Inhibitors/pharmacology
Humans
Mice
Mice, Knockout
Neovascularization, Physiologic/*drug effects
Nitric Oxide/biosynthesis/*metabolism
Nitric Oxide Synthase Type III/deficiency/metabolism
Phosphorylation/drug effects
Proto-Oncogene Proteins c-akt/metabolism
Rats
Rats, Sprague-Dawley
Research Support, Non-U.S. Gov't
Signal Transduction/*drug effects
Umbilical Veins/cytology/*drug effects/metabolism
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