Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells

• Published in: Experimental & molecular medicine Vol. 37; no. 6; pp. 588 - 600
• Main Authors: Namkoong, Seung, Lee, Seon Jin, Kim, Chun Ki, Kim, Young Mi, Chung, Hun Taeg, Lee, Hansoo, Han, Jeong A, Ha, Kwon Soo, Kwon, Young Guen, Kim, Young Myeong
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.12.2005; 생화학분자생물학회
• Subjects: Animals; Aorta; Cell Movement - drug effects; Cell Proliferation - drug effects; Cyclic AMP - metabolism; Cyclic AMP - pharmacology; Cyclic GMP - biosynthesis; Cyclic GMP - metabolism; Dinoprostone - pharmacology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzyme Inhibitors - pharmacology; Humans; Mice; Mice, Knockout; Neovascularization, Physiologic - drug effects; Nitric Oxide - biosynthesis; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - deficiency; Nitric Oxide Synthase Type III - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Umbilical Veins - cytology; Umbilical Veins - drug effects; Umbilical Veins - metabolism; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/emm.2005.72

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 PGE2 regulates angiogenesis. Treatment of human umbilical vein endothelial cells (HUVEC) with PGE2 increased angiogenesis. PGE2 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 PGE2 in angiogenesis and the signaling pathway, suggesting that cAMP is a down-stream mediator of PGE2. Furthermore, PGE2 increased endothelial cell sprouting from normal murine aortic segments, but not from eNOS-deficient ones, on Matrigel. The angiogenic effects of PGE2 were inhibited by the inhibitors of PKA, PI3K, eNOS, and soluble guanylate cyclase, but not by phospholipase C inhibitor. These results clearly show that PGE2 increased angiogenesis by activating the NO/cGMP signaling pathway through PKA/PI3K/Akt-dependent increase in eNOS activity.