Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1
Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1
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DOI：
10.1074/jbc.m703090200
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发表时间：
2008-01-25
影响因子：
4.8
通讯作者：
Donnini, Sandra
中科院分区：
文献类型：
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作者：
Finetti, Federica;Solito, Raffaella;Donnini, Sandra
前列腺素E-2 （PGE(2)）在上皮肿瘤细胞以及许多其他细胞类型中作为丝裂原发挥作用。我们研究了PGE(2)对微血管内皮细胞（毛细血管内皮细胞）的作用，目的是描述导致血管生成表型获得和新血管形成的信号通路。PGE(2) （100 nM）通过磷酸化检测，可激活成纤维细胞生长因子受体1 (FGFR-1)，但不激活血管内皮生长因子受体2。PGE(2)刺激EP3亚型受体，通过百日咳毒素消除EP3G α (i)亚基活性推断。与此结果一致的是，在缺失EP3受体的人脐静脉内皮细胞中，PGE(2)不磷酸化FGFR-1。在与其受体结合后，PGE2启动了自分泌/旁分泌信号级联反应，涉及细胞内c-Src的激活，基质金属蛋白酶（主要是MMP2）的激活，进而引起膜锚定成纤维细胞生长因子-2 （FGF-2）的动员。事实上，在不能释放FGF-2的细胞中，转染FGFR-1和EP3并不会导致FGFR-1磷酸化以响应PGE(2)。共聚焦分析强调了FGF2-FGFR-1系统的相关性，显示细胞暴露于前列腺素后受体内化。ERK1/2似乎是远端信号参与，其磷酸化对证监会抑制剂或FGFR-1阻滞剂敏感。最后，PGE(2)刺激了主动脉环的细胞迁移和毛细血管形成，而信号分子抑制剂或受体拮抗剂严重降低了这一作用。总之，本研究为FGFR-1通过FGF2参与引发PGE(2)血管生成反应提供了证据。这种信号模式类似于内皮细胞支持新生血管生长的自分泌-旁分泌机制。
Prostaglandin E-2 (PGE(2)) behaves as a mitogen in epithelial tumor cells as well as in many other cell types. We investigated the actions of PGE(2) on microvascular endothelial cells ( capillary venular endothelial cells) with the purpose of delineating the signaling pathway leading to the acquisition of the angiogenic phenotype and to new vessel formation. PGE(2) (100 nM) produced activation of the fibroblast growth factor receptor 1 (FGFR-1), as measured by its phosphorylation, but not of vascular endothelial growth factor receptor 2. PGE(2) stimulated the EP3 subtype receptor, as deduced by abrogation of EP3G alpha(i) subunit activity through pertussis toxin. Consistent with this result, in human umbilical venular endothelial cells missing the EP3 receptor, PGE(2) did not phosphorylate FGFR-1. Upon binding to its receptor, PGE2 initiated an autocrine/paracrine signaling cascade involving the intracellular activation of c-Src, activation of matrix metalloproteinase (predominantly MMP2), which in turn caused the mobilization of membrane-anchored fibroblast growth factor-2 (FGF-2). In fact, in cells unable to release FGF-2 the transfection with both FGFR-1 and EP3 did not result in FGFR-1 phosphorylation in response to PGE(2). Relevance for the FGF2-FGFR-1 system was highlighted by confocal analysis, showing receptor internalization after cell exposure to the prostanoid. ERK1/2 appeared to be the distal signal involved, its phosphorylation being sensitive to either cSrc inhibitor or FGFR-1 blocker. Finally, PGE(2) stimulated cell migration and capillary formation in aortic rings, which were severely reduced by inhibitors of signaling molecules or by receptor antagonist. In conclusion, this study provides evidence for the involvement of FGFR-1 through FGF2 in eliciting PGE(2) angiogenic responses. This signaling pattern is similar to the autocrine-paracrine mechanism which operates in endothelial cells to support neovascular growth.