Yang Ke, Doughman Yong-Qiu, Karunamuni Ganga, Gu Shi, Yang Yu-Chung, Bader David M, Watanabe Michiko
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Dev Dyn. 2009 Jan;238(1):162-70. doi: 10.1002/dvdy.21811.
Notch1 is an important regulator of intercellular interactions in cardiovascular development. We show that the nuclear-localized, cleaved and active form of Notch1, the Notch1 intracellular domain (N1ICD), appeared in mesothelial cells of the pro-epicardium during epicardial formation at looped heart stages. N1ICD was also present in mesothelial cells and mesenchymal cells specifically within the epicardium at sulcus regions. N1ICD-positive endothelial cells were detected within the nascent vessel plexus at the atrioventricular junction and within the compact myocardium (Hamburger and Hamilton stage [HH] 25-HH30). The endothelial cells expressing N1ICD were surrounded by N1ICD-positive smooth muscle cells after coronary orifice formation (HH32-HH35), while N1ICD expression was absent in the mesenchymal and mesothelial cells surrounding mature coronary vessels. We propose that differential activation of the hypoxia/HIF1-VEGF-Notch pathway may play a role in epicardial cell interactions that promote epicardial epithelial/mesenchymal transition and coronary progenitor cell differentiation during epicardial development and coronary vasculogenesis in particularly hypoxic sulcus regions.
Notch1是心血管发育过程中细胞间相互作用的重要调节因子。我们发现，Notch1的核定位、裂解且具有活性的形式，即Notch1细胞内结构域（N1ICD），在心脏成环阶段的心外膜形成过程中出现在心外膜原基的间皮细胞中。N1ICD也存在于心沟区域的心外膜内的间皮细胞和间充质细胞中。在房室交界处的新生血管丛内以及致密心肌中（汉伯格和汉密尔顿分期[HH]25 - HH30）检测到N1ICD阳性内皮细胞。在冠状动脉口形成后（HH32 - HH35），表达N1ICD的内皮细胞被N1ICD阳性平滑肌细胞包围，而在成熟冠状动脉周围的间充质细胞和间皮细胞中不存在N1ICD表达。我们提出，缺氧/HIF1 - VEGF - Notch通路的差异激活可能在心外膜细胞相互作用中发挥作用，这种相互作用在心外膜发育以及特别是在缺氧的心沟区域的冠状动脉血管生成过程中促进心外膜上皮/间充质转化和冠状动脉祖细胞分化。
