Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.
Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium.
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DOI：
10.1016/j.ydbio.2013.01.026
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发表时间：
2013-04-15
影响因子：
2.7
通讯作者：
Watanabe, Michiko
中科院分区：
文献类型：
--
作者：
Tao, Jiayi;Doughman, Yongqiu;Yang, Ke;Ramirez-Bergeron, Diana;Watanabe, Michiko
关键词：
在心脏发生过程中，一部分心外膜细胞经历上皮-间充质转化（EMT），产生的心外膜衍生细胞（EPDC）有助于冠状血管的形成。我们以前的数据显示，缺氧诱导因子-1 α（HIF-1α）在心外膜内的特定部位表达，并支持缺氧诱导因子（HIF）与冠状动脉血管发生模式之间的联系。为了更好地理解HIF在心外膜中的自分泌作用，我们将腺病毒介导的组成型活性HIF-1α（AdcaHIF 1 α）的表达转导到血管前体所在的胚胎禽心外膜中。我们发现，将CaHIF 1 α引入心外膜间皮可阻止EPDCs正确迁移到心肌中。体外胶原凝胶分析和离体器官培养数据进一步证实，AdcaHIF 1 α感染削弱了EPDCs的侵袭能力。然而，心外膜细胞进行EMT的能力增强，而EPDCs在心外膜下的运动及其向平滑肌细胞的分化不被caHIF 1 α破坏。我们还发现，在将caHIF 1 α导入心外膜细胞后，Flt-1（VEGFR 1）的转录水平（可作为VEGF信号传导抑制剂）增加了数倍。阻断心外膜细胞中VEGF通路的激活概括了对EPDC侵袭的抑制。这些结果表明，CaHIF 1 α介导的Flt-1上调，阻断了VEGF通路的激活，是抑制EPDC心肌迁移的原因。总之，我们的研究表明，HIF信号可能调节心外膜EMT的程度和EPDC迁移到心肌的程度，这两者在早期心脏血管发生期间可能对冠状动脉血管形成至关重要。这些信号可以解释为什么较大的冠状动脉出现并留在心外膜表面。
During cardiogenesis, a subset of epicardial cells undergoes epithelial-mesenchymal-transition (EMT) and the resulting epicardial derived cells (EPDCs) contribute to the formation of coronary vessels. Our previous data showed hypoxia inducible factor-1α (HIF-1α) expression at specific sites within the epicardium and support a link between hypoxia inducible factors (HIFs) and the patterning of coronary vasculogenesis. To better understand the autocrine role of HIFs in the epicardium, we transduced adenovirus mediated expression of constitutively active HIF-1α (AdcaHIF1α) into the embryonic avian epicardium where the vascular precursors reside. We found that introducing caHIF1α into the epicardial mesothelium prevented EPDCs from proper migration into the myocardium. In vitro collagen gel assays and ex vivo organ culture data further confirmed that infection with AdcaHIF1α impaired the ability of EPDCs to invade. However, the proficiency of epicardial cells to undergo EMT was enhanced while the movement of EPDCs within the sub-epicardium and their differentiation into smooth muscle cells were not disrupted by caHIF1α. We also showed that the transcript level of Flt-1 (VEGFR1), which can act as a VEGF signaling inhibitor, increased several fold after introducing caHIF1α into epicardial cells. Blocking the activation of the VEGF pathway in epicardial cells recapitulated the inhibition of EPDC invasion. These results suggest that caHIF1α mediated up-regulation of Flt-1, which blocks the activation of the VEGF pathway, is responsible for the inhibition of EPDC myocardial migration. In conclusion, our studies demonstrate that HIF signaling potentially regulates the degree of epicardial EMT and the extent of EPDC migration into the myocardium, both of which are likely critical in patterning the coronary vasculature during early cardiac vasculogenesis. These signals could explain why the larger coronaries appear and remain on the epicardial surface.
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DOI：
10.1083/jcb.200709114
发表时间：
2008-06-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kappas NC;Zeng G;Chappell JC;Kearney JB;Hazarika S;Kallianos KG;Patterson C;Annex BH;Bautch VL
通讯作者：
Bautch VL
影响因子：
9.8
作者：
Han, Yu;Yang, Ke;Proweller, Aaron;Zhou, Guangjin;Jain, Mukesh K.;Ramirez-Bergeron, Diana L.
通讯作者：
Ramirez-Bergeron, Diana L.
影响因子：
20.3
作者：
Kim, Jun-Sub;Kim, Jae-Gyu;Park, Jae-Bong
通讯作者：
Park, Jae-Bong
影响因子：
--
作者：
HIRUMA, T;HIRAKOW, R
通讯作者：
HIRAKOW, R
影响因子：
4.8
作者：
Gerber, HP;Condorelli, F;Ferrara, N
通讯作者：
Ferrara, N