REGULATION OF VASCULAR REMODELING IN ADULT MYOCARDIUM BY THYROID HORMONES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的目的是研究成人心脏血管生长的细胞和分子机制。在正常生长和成熟过程中，微循环血管的增殖与心肌细胞的肥大相平行。然而，许多研究表明，血管生长受损和血管疾病在病理性心肌肥厚中起主要作用。这可能涉及冠状动脉密度降低和血流调节受损。最近的研究提供了更多关于血管生长受损在病理性心肌肥厚演变中的作用的机制信息。事实上，似乎在生理性心肌肥厚时阻断血管生长会导致转化为病理表型。众所周知，甲状腺激素(TH)可以刺激血管生长并激活Akt途径。然而，到目前为止，心脏血管生长还没有从机械上与Akt途径联系起来。 ____________________ 在这项研究中，我们将验证TH通过Akt信号通路促进成年心肌血管生成的假设，这一过程伴随着内皮祖细胞的动员。为了验证这一假设，目标1将广泛描述T3诱导成人心脏血管生成的细胞特征，并确定Akt信号的作用。目的2将使用来自目标1的动物来研究T3对内皮祖细胞动员的影响。目的探讨PI3K-Akt-HIF-1信号通路在体外血管生成过程中TH诱导的血管重塑和血管完整性中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to study the cellular and molecular mechanisms of vascular growth in adult hearts. Proliferation of microcirculatory vessels parallels myocyte hypertrophy during normal growth and maturation. Many studies, however, have demonstrated that impaired vascular growth and vascular disease play a major role in pathologic cardiac hypertrophy. This may involve reduced density of coronary vessels and impaired regulation of blood flow. Recent studies have provided more mechanistic information about the role of impaired vascular growth in the evolution of pathologic cardiac hypertrophy. Indeed, it appears that blocking vascular growth during physiological cardiac hypertrophy results in conversion to a pathologic phenotype. Thyroid hormones (THs) are known to stimulate vascular growth and activate the Akt pathway. To this point, however, cardiac vascular growth has not been mechanistically linked to Akt pathway. ____________________ In this study, we will test the hypothesis that TH's promote angiogenesis via an Akt signaling pathway in adult myocardium and this process is accompanied by mobilization of endothelial progenitor cells. To test this hypothesis Aim 1 will extensively characterize the cellular features of T3-induced angiogenesis in adult heart and determine the role of Akt signaling. Aim 2 will use the animals from Aim 1 to investigate the effect of T3 on the mobilization of endothelial progenitor cells. Aim 3 will explore the role of the PI3K-Akt-HIF-1 signaling pathway in TH induced vascular remodeling and vessel integrity during the angiogenic process in vitro.