title: Prostaglandin E2 promotes endothelial differentiation from bone marrow-derived cells through AMPK activation.
abstract: Prostaglandin E2 (PGE2) has been reported to modulate angiogenesis, the process of new blood vessel formation, by promoting proliferation, migration and tube formation of endothelial cells. Endothelial progenitor cells are known as a subset of circulating bone marrow mononuclear cells that have the capacity to differentiate into endothelial cells. However, the mechanism underlying the stimulatory effects of PGE2 and its specific receptors on bone marrow-derived cells (BMCs) in angiogenesis has not been fully characterized. Treatment with PGE2 significantly increased the differentiation and migration of BMCs. Also, the markers of differentiation to endothelial cells, CD31 and von Willebrand factor, and the genes associated with migration, matrix metalloproteinases 2 and 9, were significantly upregulated. This upregulation was abolished by dominant-negative AMP-activated protein kinase (AMPK) and AMPK inhibitor but not protein kinase, a inhibitor. As a functional consequence of differentiation and migration, the tube formation of BMCs was reinforced. Along with altered BMCs functions, phosphorylation and activation of AMPK and endothelial nitric oxide synthase, the target of activated AMPK, were both increased which could be blocked by EP4 blocking peptide and simulated by the agonist of EP4 but not EP1, EP2 or EP3. The pro-angiogenic role of PGE2 could be repressed by EP4 blocking peptide and retarded in EP4(+/-) mice. Therefore, by promoting the differentiation and migration of BMCs, PGE2 reinforced their neovascularization by binding to the receptor of EP4 in an AMPK-dependent manner. PGE2 may have clinical value in ischemic heart disease.
authors.affiliation: Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Zhenjiu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Chenglai
authors.initials: C
authors.lastname: Fu
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Song
authors.forename: Chenghong
authors.initials: C
authors.lastname: Li
authors.forename: Minghui
authors.initials: M
authors.lastname: Zou
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D011494:Protein Kinases; D055372:AMP-Activated Protein Kinases; D015232:Dinoprostone