Hypoxia Supports Epicardial Cell Differentiation in Vascular Smooth Muscle Cells through the Activation of the TGFβ Pathway.
Hypoxia Supports Epicardial Cell Differentiation in Vascular Smooth Muscle Cells through the Activation of the TGFβ Pathway.
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DOI：
10.3390/jcdd5020019
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发表时间：
2018-04-13
影响因子：
2.4
通讯作者：
Ramírez-Bergeron D
中科院分区：
文献类型：
--
作者：
Tao J;Barnett JV;Watanabe M;Ramírez-Bergeron D
心外膜衍生细胞（Epicardium-derived cells，EPDCs）是一类重要的多能心血管祖细胞。EPDCs通过上皮-间充质转化（EMT）侵入心外膜和心肌，并进一步分化为冠状动脉血管形成所需的几种细胞类型。我们以前的研究表明，心外膜缺氧诱导因子（HIF）信号介导的血管前体细胞的入侵至关重要的图案冠状动脉血管。在这里，我们研究了缺氧（1%的氧气）对EPDC分化为血管平滑肌细胞（VSMCs）的调节作用。结果：缺氧刺激EMT，并增强小鼠心外膜细胞培养中几种VSMC标志物的表达。通过抑制转化生长因子β（TGFβ）受体I特异性阻断这种刺激。进一步分析表明，低氧可增加TGFβ 1配体的表达水平和TGFβ受体II的磷酸化水平，提示TGFβ途径在低氧刺激的VSMC分化中起着不可或缺的作用。我们进一步证明了非经典RhoA/Rho激酶（ROCK）通路作为TGFβ的主要下游效应物调节缺氧对VSMC分化的影响。结论：我们的研究结果揭示了心外膜HIF通过非经典TGFβ信号促进其分化为VSMCs而介导冠状动脉血管发生的新作用。这些数据阐明了冠状动脉血管的模式受到心外膜缺氧信号的影响。
Epicardium-derived cells (EPDCs) are an important pool of multipotent cardiovascular progenitor cells. Through epithelial-to-mesenchymal-transition (EMT), EPDCs invade the subepicardium and myocardium and further differentiate into several cell types required for coronary vessel formation. We previously showed that epicardial hypoxia inducible factor (HIF) signaling mediates the invasion of vascular precursor cells critical for patterning the coronary vasculature. Here, we examine the regulatory role of hypoxia (1% oxygen) on EPDC differentiation into vascular smooth muscle cells (VSMCs). Results: Hypoxia stimulates EMT and enhances expression of several VSMC markers in mouse epicardial cell cultures. This stimulation is specifically blocked by inhibiting transforming growth factor-beta (TGFβ) receptor I. Further analyses indicated that hypoxia increases the expression level of TGFβ-1 ligand and phosphorylation of TGFβ receptor II, suggesting an indispensable role of the TGFβ pathway in hypoxia-stimulated VSMC differentiation. We further demonstrate that the non-canonical RhoA/Rho kinase (ROCK) pathway acts as the main downstream effector of TGFβ to modulate hypoxia’s effect on VSMC differentiation. Conclusion: Our results reveal a novel role of epicardial HIF in mediating coronary vasculogenesis by promoting their differentiation into VSMCs through noncanonical TGFβ signaling. These data elucidate that patterning of the coronary vasculature is influenced by epicardial hypoxic signals.
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影响因子：
4.8
作者：
Clark CR;Robinson JY;Sanchez NS;Townsend TA;Arrieta JA;Merryman WD;Trykall DZ;Olivey HE;Hong CC;Barnett JV
通讯作者：
Barnett JV
影响因子：
20.1
作者：
Compton, Leigh A.;Potash, Dru A.;Barnett, Joey V.
通讯作者：
Barnett, Joey V.
DOI：
10.1016/j.bbamcr.2013.02.029
发表时间：
2013-06
影响因子：
5.1
作者：
Han, Wei-Qing;Zhu, Qing;Hu, Junping;Li, Pin-Lan;Zhang, Fan;Li, Ningjun
通讯作者：
Li, Ningjun
影响因子：
2.5
作者：
Guadix, JA;Carmona, R;Pérez-Pomares, JM
通讯作者：
Pérez-Pomares, JM
影响因子：
5
作者：
Braitsch, Caitlin M.;Kanisicak, Onur;van Berlo, Jop H.;Molkentin, Jeffery D.;Yutzey, Katherine E.
通讯作者：
Yutzey, Katherine E.