Spatial and temporal regulation of coronary vessel formation by calcineurin-NFAT signaling.
Spatial and temporal regulation of coronary vessel formation by calcineurin-NFAT signaling.
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DOI：
10.1242/dev.037903
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Chang CP
中科院分区：
文献类型：
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作者：
Zeini M;Hang CT;Lehrer-Graiwer J;Dao T;Zhou B;Chang CP
冠状脉管系统的形成需要内皮、心外膜衍生的平滑肌和下面的心肌细胞之间的相互信号传导。我们的研究表明，钙调神经磷酸酶-NFAT 信号在内皮细胞中的特定时间窗口发挥作用，调节冠状血管的发育。暴露于抑制钙调神经磷酸酶活性的环孢菌素（CsA）的小鼠胚胎未能发育出正常的冠状血管系统。为了确定钙调神经磷酸酶在冠状血管生成中发挥作用的细胞位点，我们在内皮细胞、心外膜细胞和心肌细胞中删除了钙调神经磷酸酶。内皮细胞中钙调神经磷酸酶-NFAT 信号传导的破坏导致冠状动脉血管生成失败，重现了在 CsA 处理的胚胎中观察到的冠状动脉表型。相比之下，心外膜细胞或心肌细胞中钙调神经磷酸酶的缺失对早期胚胎发生期间的冠状脉管系统没有影响。为了确定 NFAT 信号传导的时间要求，我们在 E9.5 至 E12.5 的重叠窗口用 CsA 处理发育中的胚胎，并在 E12.5 时检查冠状动脉发育。这些实验表明，钙调神经磷酸酶-NFAT 信号在 E10.5 至 E11.5 之间发挥作用，调节冠状动脉血管生成。与这些体内观察结果一致，在组织培养的特定时间窗口内暴露于 CsA 的内皮细胞无法形成管状结构，并且它们对 VEGF-A 的细胞反应减弱。因此，我们的研究证明了 NFAT 信号传导对冠状血管血管生成的特定时间和空间要求。这些要求与 NFAT 信号在外周体细胞血管生成中的作用不同，提供了不同血管床的环境影响体内内皮细胞对血管生成刺激的反应的例子。
Formation of the coronary vasculature requires reciprocal signaling between endothelial, epicardially-derived smooth muscle and underlying myocardial cells. Our studies show that calcineurin-NFAT signaling functions in endothelial cells at specific time windows to regulate coronary vessel development. Mouse embryos exposed to cyclosporine (CsA), which inhibits calcineurin phosphatase activity, failed to develop normal coronary vasculature. To determine the cellular site where calcineurin functions for coronary angiogenesis, we deleted calcineurin in endothelial, epicardial and myocardial cells. Disruption of calcineurin-NFAT signaling in endothelial cells resulted in failure of coronary angiogenesis, recapitulating the coronary phenotype observed in CsA-treated embryos. In contrast, deletion of calcineurin in either epicardial or myocardial cells had no effects on coronary vasculature during early embryogenesis. To define the temporal requirement for NFAT signaling, we treated developing embryos with CsA at overlapping windows from E9.5 to E12.5 and examined coronary development at E12.5. These experiments demonstrate that calcineurin-NFAT signaling functions between E10.5 to E11.5 to regulate coronary angiogenesis. Consistent with these in vivo observations, endothelial cells exposed to CsA within specific time windows in tissue culture were unable to form tubular structures and their cellular responses to VEGF-A were blunted. Thus, our studies demonstrate specific temporal and spatial requirements of NFAT signaling for coronary vessel angiogenesis. These requirements are distinct from the roles of NFAT signaling in the angiogenesis of peripheral somatic vessels, providing an example of the environmental influence of different vascular beds on the in vivo endothelial responses to angiogenic stimuli.