Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo
Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo
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DOI：
10.1074/jbc.m701214200
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发表时间：
2007-06-08
影响因子：
4.8
通讯作者：
Pozzi, Ambra
中科院分区：
文献类型：
--
作者：
Rao, Reena;Redha, Reyadh;Pozzi, Ambra
前列腺素E2（PGE（2））是环氧合酶的主要产物，通过与四种G蛋白偶联受体（EP 1 -4）结合发挥其功能，并参与调节血管生成。本研究检测了EP 4受体在调节内皮细胞增殖、迁移和小管形成中的作用。从EP 4（flox/flox）小鼠分离原代肺微血管内皮细胞，并用腺Cre病毒使其对EP 4受体无效。然而，用PGE（2）或EP 4选择性激动剂PGE（1）-OH和ONO-AE 1 -329处理在对照腺病毒转导的内皮EP 4（flox/flox）细胞中诱导迁移、小管形成、ERK激活和cAMP产生，在腺病毒转导的EP 4（flox/flox）细胞中没有观察到任何影响。EP 4激动剂诱导的内皮细胞迁移被ERK抑制，但PKA抑制剂不抑制，这说明PGE（2）诱导的内皮细胞迁移和EP 4介导的ERK信号传导之间存在功能性联系。最后，PGE 2以及PGE 1-OH和ONO-AE 1 - 329也在体内海绵测定中促进血管生成，提供了EP 4受体介导体内新生血管形成的证据。
Prostaglandin E2 (PGE(2)), a major product of cyclooxygenase, exerts its functions by binding to four G protein-coupled receptors (EP1-4) and has been implicated in modulating angiogenesis. The present study examined the role of the EP4 receptor in regulating endothelial cell proliferation, migration, and tubulogenesis. Primary pulmonary microvascular endothelial cells were isolated from EP4(flox/flox) mice and were rendered null for the EP4 receptor with adenoCre virus. Whereas treatment with PGE(2) or the EP4 selective agonists PGE(1)-OH and ONO-AE1-329 induced migration, tubulogenesis, ERK activation and cAMP production in control adenovirus-transduced endothelial EP4(flox/flox) cells, no effects were seen in adenoCre-transduced EP4(flox/flox) cells. The EP4 agonist-induced endothelial cell migration was inhibited by ERK, but not PKA inhibitors, defining a functional link between PGE(2)-induced endothelial cell migration and EP4-mediated ERK signaling. Finally, PGE2, as well as PGE1-OH and ONO-AE1 -329, also promoted angiogenesis in an in vivo sponge assay providing evidence that the EP4 receptor mediates de novo vascularization in vivo.