Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
PLoS One. 2011;6(8):e23554. doi: 10.1371/journal.pone.0023554. Epub 2011 Aug 18.
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.
前列腺素 E2（PGE2）已被报道通过促进内皮细胞的增殖、迁移和管形成来调节血管生成，即新血管形成的过程。内皮祖细胞被认为是循环骨髓单核细胞的一个亚群，具有分化为内皮细胞的能力。然而，PGE2 及其特定受体对骨髓来源细胞（BMCs）在血管生成中的刺激作用的机制尚未完全阐明。PGE2 的治疗显著增加了 BMCs 的分化和迁移。此外，内皮细胞分化的标志物 CD31 和血管性血友病因子，以及与迁移相关的基因，基质金属蛋白酶 2 和 9，均显著上调。这种上调被 AMP 激活的蛋白激酶（AMPK）的显性负性和 AMPK 抑制剂而非蛋白激酶抑制剂所阻断。作为分化和迁移的功能结果，BMCs 的管形成得到了加强。随着 BMCs 功能的改变，AMPK 和内皮型一氧化氮合酶的磷酸化和激活均增加，这可被 EP4 阻断肽阻断，并可通过 EP4 的激动剂模拟，但不能通过 EP1、EP2 或 EP3 模拟。PGE2 的促血管生成作用可被 EP4 阻断肽抑制，并在 EP4(+/-) 小鼠中被延迟。因此，PGE2 通过与 EP4 受体结合，以 AMPK 依赖的方式促进 BMCs 的分化和迁移，从而增强其新生血管形成。PGE2 在缺血性心脏病中可能具有临床价值。
