Sugishita Yasuyuki, Leifer David W, Agani Faton, Watanabe Michiko, Fisher Steven A
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Dev Biol. 2004 Sep 15;273(2):285-96. doi: 10.1016/j.ydbio.2004.05.036.
We proposed a model in which myocardial hypoxia triggers the apoptosis-dependent remodeling of the avian outflow tract (OFT) in the transition of the embryo to a dual circulation. In this study, we examined hypoxia-dependent signaling in cardiomyocyte apoptosis and outflow tract remodeling. The hypoxia-inducible transcription factor HIF-1alpha was specifically present in the nuclei of OFT cardiomyocytes from stages 25-32, the period of hypoxia-dependent OFT remodeling. HIF-1alpha expression was sensitive to changes in ambient oxygen concentrations, while its dimerization partner HIF-1beta was constitutively expressed. There was not a simple relationship between HIF-1alpha expression and apoptosis. Apoptotic cardiomyocytes were detected in HIF-1alpha-positive and -negative regions, and a hypoxic stimulus sufficient to induce nuclear accumulation of HIF-1alpha did not induce cardiomyocyte apoptosis. The hypoxia-dependent expression of the vascular endothelial growth factor receptor (VEGFR2) in the distal OFT myocardium may be protective as cardiomyocyte apoptosis in the early stages (25-30) of OFT remodeling was absent from this region. Furthermore, recombinant adenoviral-mediated expression of dominant negative Akt, an inhibitor of tyrosine kinase receptor signaling, augmented cardiomyocyte apoptosis in the OFT and constitutively active Akt suppressed it. Adenovirus-mediated forced expression of VEGF165 induced conotruncal malformation such as double outlet right ventricle (DORV) and ventricular septal defect (VSD), similar to defects observed when apoptosis-dependent remodeling of the OFT was specifically targeted. We conclude that normal developmental remodeling of the embryonic avian cardiac OFT involves hypoxia/HIF-1-dependent signaling and cardiomyocyte apoptosis. Autocrine signaling through VEGF/VEGFR2 and Akt provides survival signals for the hypoxic OFT cardiomyocytes, and regulated VEGF signaling is required for the normal development of the OFT.
我们提出了一个模型，其中在胚胎向双循环转变过程中，心肌缺氧触发了禽类流出道（OFT）依赖凋亡的重塑。在本研究中，我们检测了心肌细胞凋亡和流出道重塑中依赖缺氧的信号传导。缺氧诱导转录因子HIF-1α特异性存在于第25至32阶段OFT心肌细胞的细胞核中，这是OFT依赖缺氧重塑的时期。HIF-1α表达对环境氧浓度变化敏感，而其二聚化伴侣HIF-1β则持续表达。HIF-1α表达与凋亡之间不存在简单的关系。在HIF-1α阳性和阴性区域均检测到凋亡心肌细胞，足以诱导HIF-1α核积累的缺氧刺激并未诱导心肌细胞凋亡。OFT远端心肌中血管内皮生长因子受体（VEGFR2）的缺氧依赖性表达可能具有保护作用，因为在OFT重塑的早期阶段（25至30），该区域不存在心肌细胞凋亡。此外，重组腺病毒介导的显性负性Akt（酪氨酸激酶受体信号抑制剂）的表达增加了OFT中的心肌细胞凋亡，而组成型活性Akt则抑制了这种凋亡。腺病毒介导的VEGF165强制表达诱导了诸如右心室双出口（DORV）和室间隔缺损（VSD）等圆锥干畸形，类似于当OFT依赖凋亡的重塑被特异性靶向时观察到的缺陷。我们得出结论，胚胎禽类心脏OFT的正常发育重塑涉及缺氧/HIF-1依赖性信号传导和心肌细胞凋亡。通过VEGF/VEGFR2和Akt的自分泌信号为缺氧的OFT心肌细胞提供存活信号，并且OFT的正常发育需要受调控的VEGF信号传导。
