PAR2-SMAD3 in microvascular endothelial cells is indispensable for vascular stability via tissue factor signaling

被引:20
作者
Arderiu, Gemma [1 ]
Espinosa, Sonia
Pena, Esther
Aledo, Rosa
Badimon, Lina [1 ]
机构
[1] UAB, Hosp St Pau, Cardiovasc Res Ctr CSIC ICCC, Barcelona 08025, Spain
关键词
angiogenesis; microvascular endothelial cells; SMAD3; tissue factor; PAR2; BETA-INDUCED TRANSCRIPTION; ACTIVATED RECEPTOR 2; BREAST-CANCER CELLS; FACTOR VIIA; ATHEROSCLEROTIC PLAQUES; MICROVESSEL FORMATION; MDA-MB-231; CELLS; GENE-EXPRESSION; UP-REGULATION; ETS FAMILY;
D O I
10.1093/jmcb/mjv065
中图分类号
Q2 [细胞生物学];
学科分类号
071013 [干细胞生物学];
摘要
Tissue factor (TF) signaling regulates gene expression and protein synthesis leading to the modulation of cell function. Recently, we have demonstrated in microvascular endothelial cells (mECs) that TF signaling induces activation of ETS1 transcription factor. Because combinatorial control is a characteristic property of ETS family members, involving the interaction between ETS1 and other transcription factors, here we investigate whether additional transcription factors are involved in TF-induced angiogenesis. We show by in vitro and in vivo experiments that in addition to ETS1, SMAD3 contributes to tube-like stabilization induced by TF in mECs. Whereas the ability of TF-overexpressing cells to induce gene expression through ETS1 is dependent on AKT signaling, SMAD3 induces ETS1 by an alternative AKT-independent pathway. Moreover, while TF-AKT-ETS1 pathway to induce CCL2 is PAR2-independent, PAR2 is required for TF-SMAD3-induced CCL2 expression. PAR2-dependent activation of SMAD3 is mediated by PKC phosphorylation. In addition, disruption of SMAD3 expression in mECs reduces ERK1/2 phosphorylation and decreases target gene promoter activity. In conclusion, in mECs TF-induced angiogenesis seems to be the result of two signaling pathways: TF-induced microvessel formation is regulated through beta 1 integrin-AKT-ETS1; and TF-induced microvessel stabilization is regulated via PAR2-SMAD3 that is indispensable for the maintenance of vascular integrity.
引用
收藏
页码:255 / 270
页数:16
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