Transcriptional Control of Early Coronary Vascular Development

描述(申请人提供)：许多先天性和获得性疾病，如心血管畸形、糖尿病、高血压、肺动静脉疾病、外周血管疾病以及心肌缺血和梗塞，都会发生血管异常和重构。血管发育缺陷已被认为是胎儿死亡的主要原因。然而，对于正常血管发育的机制，尤其是关于内皮细胞和血管平滑肌细胞的前体以及决定其对血管表型的承诺的因素，人们知之甚少。此外，这些前体随后发展为进一步多样性的遗传机制还没有被很好地理解。这些机制可能对维持健康的血管系统和修复成熟生物体的损伤很重要。在哺乳动物中，冠状动脉血管的发育依赖于心前膜内的暂时性早期胚胎结构。心外膜内的细胞在心脏表面迁移，形成心外膜，随后形成心外膜下间充质细胞(SEMC)。SEMC对心脏发育的多个方面都很重要，并形成由成纤维细胞、内皮细胞和平滑肌细胞组成的整个冠状动脉血管系统。我们实验室最近的研究确定了两种转录因子，血清反应因子(SRF)和GATA4，在控制心前膜发育方面发挥了重要作用。这一应用的重点是确定其中一个因子SRF在调控心外膜冠状动脉血管前体细胞向血管发育所需的基因表达程序中的作用。我们将利用我们最近建立的转基因SRF条件基因敲除动物，来解决最初SRF是心前膜形成所必需的假说。这些研究的结果不仅将阐明控制冠状动脉早期血管发育的潜在转录调控机制，而且还将识别可能导致心脏再生治疗应用的冠状动脉血管前体干细胞。

DESCRIPTION (provided by applicant): Vascular anomalies and remodeling occur in many congenital and acquired diseases such as cardiovascular malformations, diabetes, hypertension, pulmonary diseases of arteries and veins, peripheral vascular disease and myocardial ischemia and infarction. Defects in vascular development have been identified as a major cause of fetal demise. However, there is a paucity of knowledge of the mechanisms that underlie normal vascular development and particularly regarding the progenitors of endothelial and vascular smooth muscle cells and factors that determine their commitment to blood vessel phenotypes. Additionally, the genetic mechanisms by which these precursors subsequently develop further diversity are not well understood. These mechanisms are likely important for the maintenance of healthy vascular systems and for repair of damage in mature organisms. In mammals coronary vascular development is dependent on transient early embryonic structures within the proepicardium. Cells within the proepicardium migrate over the surface of the heart forming the epicardium and subsequently subepicardial mesenchymal cells (SEMC). SEMC are important for multiple aspects of heart development and give rise to the entire coronary vasculature consisting of fibroblasts, endothelial, and smooth muscle cells. Recent studies in our labs have determined that two transcription factors, Serum Response Factor (SRF) and GATA4, play seminal roles in controlling development of the proepicardium. The focus of this application is to determine the role of one of these factors, SRF, in regulating programs of gene expression required for commitment of proepicardial coronary vascular progenitor cells to vascular development. We will take advantage of transgenic SRF conditional gene knockout animals, recently developed by us, to address the hypothesis that initially SRF is required for formation of the proepicardium. The results of these studies will not only elucidate the underlying transcriptional regulatory mechanisms controlling early coronary vascular development, but should also identify coronary vascular precursor stem cells that may have the potential to lead to therapeutic applications in cardiac regeneration.