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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093160-02
Application #
7851361
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Gao, Yunling
Project Start
2009-07-01
Project End
2010-12-31
Budget Start
2010-07-01
Budget End
2010-12-31
Support Year
2
Fiscal Year
2010
Total Cost
$42,259
Indirect Cost
Name
University of South Dakota
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069
Bollinger, Stephen S; Weltman, Nathen Y; Gerdes, A Martin et al. (2015) T3 supplementation affects ventilatory timing & glucose levels in type 2 diabetes mellitus model. Respir Physiol Neurobiol 205:92-8
Chen, Yue-Feng; Weltman, Nathan Y; Li, Xiang et al. (2013) Improvement of left ventricular remodeling after myocardial infarction with eight weeks L-thyroxine treatment in rats. J Transl Med 11:40
Weltman, Nathan Y; Ojamaa, Kaie; Savinova, Olga V et al. (2013) Restoration of cardiac tissue thyroid hormone status in experimental hypothyroidism: a dose-response study in female rats. Endocrinology 154:2542-52
Chen, Yue-Feng; Pottala, James V; Weltman, Nathan Y et al. (2012) Regulation of gene expression with thyroid hormone in rats with myocardial infarction. PLoS One 7:e40161
Weltman, Nathan Y; Wang, Dajun; Redetzke, Rebecca A et al. (2012) Longstanding hyperthyroidism is associated with normal or enhanced intrinsic cardiomyocyte function despite decline in global cardiac function. PLoS One 7:e46655
Chen, Jinghai; Ortmeier, Steven B; Savinova, Olga V et al. (2012) Thyroid hormone induces sprouting angiogenesis in adult heart of hypothyroid mice through the PDGF-Akt pathway. J Cell Mol Med 16:2726-35
Savinova, Olga V; Liu, Yingheng; Aasen, Garth A et al. (2011) Thyroid hormone promotes remodeling of coronary resistance vessels. PLoS One 6:e25054