REGULATION OF VASCULAR REMODELING IN ADULT MYOCARDIUM BY THYROID HORMONES

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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.