Thyroid hormone regulation of vasculature in adult myocardium

甲状腺激素对成人心肌脉管系统的调节

基本信息

批准号：
8301086
负责人：
ANTHONY Martin GERDES
金额：
$ 35.91万
依托单位：
NEW YORK INST OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301086
关键词：
Thyroid hormone regulation vasculature adult

项目摘要

DESCRIPTION (provided by applicant): Interventions that may stimulate or regulate healthy cardiac vessel growth are of considerable clinical relevance. Research conducted primarily on tumor growth and organ development has identified two major cellular mechanisms of angiogenesis: sprouting angiogenesis (SA) and intussusceptive angiogenesis (IA). SA involves sprouting and proliferation of new capillaries from existing vessels and IA involves septation and division of existing vessels with limited cell proliferation. The relative contribution of SA and IA to angiogenesis induced in adult heart is unknown primarily due to the lack of a good animal model. After demonstrating that hypothyroidism induced by either thyroidectomy or propylthioruacil (PTU) leads to a dramatic loss of myocardial arterioles within 6 weeks, we have shown a robust increase in myocardial arterioles within 1.5 days after initiating T3 treatment in hypothyroid animals. Cell proliferation was minimal at 1.5 days but increased dramatically by day 3. This suggests that IA of arterioles plays an early role and is followed by SA. This model will be exploited to study the cellular and molecular mechanisms of capillary and arteriolar growth in adult hearts. This proposal will test the overall hypothesis that thyroid hormones promote myocardial angiogenesis by sprouting angiogenesis and intussusceptive angiogenesis via an Akt dependent signaling mechanism. Pericytes, poorly understood but very common cells in adult heart, likely play a key role in the angiogenic process and will be examined in detail. Aim 1 will use the PTU+T3 model to examine the cellular mechanisms of rapid angiogenesis in adult heart. We hypothesize that PTU+T3 in adult mice triggers rapid and robust proliferation of myocardial capillaries and arterioles, allowing detailed examination of the growth process. Confocal, scanning, and transmission microscopy will be used to achieve the results in this aim. Immuno-markers for cell type and markers of proliferation will be used in the confocal analyses. Aim 2 will examine the role of Akt in the rapid angiogenic response induced in adult heart by T3 and in vessel loss from hypothyroidism. We hypothesize that Akt signaling is increased during T3 mediated angiogenesis and Akt inhibition prevents the associated angiogenesis. Conversely, reduced Akt-eNOS-NO in hypothyroidism leads to vessel loss. Aim 3 will explore the role of Akt signaling in T3 induced vascular remodeling and vessel integrity during the angiogenic process in vitro. We will use a novel model allowing direct observation of sprouting angiogenesis from cultured tissue pieces obtained from hearts used in Aims 1 and 2 to test the hypothesis that Akt is involved in thyroid hormone-mediated angiogenesis. Cultured endothelial cells will also be used to examine the role of T3 mediated Akt signaling in proliferation, migration, and tube formation. We will inhibit Akt signaling in vitro to investigate the role of this pathway in the above-mentioned angiogenic processes. Thus, the proposed work will provide important new information about the cellular and molecular mechanisms of vessel growth in adult heart. PUBLIC HEALTH RELEVANCE: Low thyroid function, which leads to vascular impairment in heart and brain, is believed to affect 5% of the US population and 10% of postmenopausal women. The cellular and molecular mechanisms by which thyroid hormones regulate cardiac vascular growth are poorly understood and will be investigated in the proposed work.

描述（由申请人提供）：可能刺激或调节健康心脏血管生长的干预措施具有相当大的临床相关性。主要关于肿瘤生长和器官发育进行的研究已经确定了血管生成的两种主要细胞机制：发芽血管生成（SA）和肠tussus utsusepsutige the tussuspective Expiogenesofic（IA）。 SA涉及来自现有血管的新毛细血管的发芽和增殖，IA涉及分隔和分裂现有细胞增殖的现有血管。 SA和IA对成人心脏诱导的血管生成的相对贡献主要是由于缺乏良好的动物模型。在证明甲状腺切除术或丙硫代（PTU）诱导的甲状腺功能减退症后，在6周内导致心肌动脉造成巨大损失，我们在1.5天内在1.5天内促进了在抑制性动物中T3治疗后1.5天内的心肌动脉急剧增加。细胞增殖在1.5天时最小，但在第3天之前急剧增加。这表明小动脉的IA起早期作用，其次是SA。该模型将被利用以研究成人心脏中毛细血管和小动脉生长的细胞和分子机制。该建议将检验总体假设，即甲状腺激素通过通过AKT依赖性信号传导机制发芽和肠us依血管生成来促进心肌血管生成。周细胞了解不足，但在成人心脏中非常常见的细胞，可能在血管生成过程中起关键作用，并将详细检查。 AIM 1将使用PTU+T3模型来检查成人心脏快速血管生成的细胞机制。我们假设成年小鼠中的PTU+T3触发了心肌毛细血管和小动脉的快速而稳健的增殖，从而详细检查了生长过程。共聚焦，扫描和传输显微镜将用于实现此目标的结果。共聚焦分析将使用用于细胞类型的免疫标记和增殖标记。 AIM 2将检查AKT在T3中诱导的成人心脏的快速血管生成反应中的作用以及甲状腺功能减退症的血管丧失。我们假设在T3介导的血管生成期间，AKT信号传导增加，而AKT抑制可防止相关的血管生成。相反，甲状腺功能减退的Akt-Enos-No降低导致血管损失。 AIM 3将探讨Akt信号在体外血管生成过程中T3诱导的血管重塑和血管完整性中的作用。我们将使用一种新型模型，可以直接观察从AIM 1和2中使用的心脏获得的培养组织碎片发芽的血管生成，以检验Akt参与甲状腺激素介导的血管生成的假设。培养的内皮细胞也将用于检查T3介导的Akt信号传导在增殖，迁移和管形成中的作用。我们将在体外抑制AKT信号传导，以研究该途径在上述血管生成过程中的作用。因此，拟议的工作将提供有关成人心脏血管生长的细胞和分子机制的重要新信息。公共卫生相关性：甲状腺功能较低，导致心脏和大脑的血管障碍，据信会影响美国5％的人口和绝经后妇女的10％。甲状腺激素调节心脏血管生长的细胞和分子机制知之甚少，并将在拟议的工作中研究。