One of the key goals in cardiac regeneration is to establish new myocardium that is as close as possible to normal myocardium, both structurally and functionally. Normal mammalian myocardium has anintricate network of capillaries, with each myocyte next to at least one capillary, and endothelial-cardiomyocyte signaling in myocardium regulates not only development of the myocardium, but also myocytefunction in adult myocardium. Ultimately, achieving the goal of regenerating myocardium will require not only restoration of viable cardiomyocytes and endothelial cells, but promoting the intricate structural relationship ofmyocytes and the microvasculature. The primary significance of these experiments is to advance understanding of the interactions of cardiomyocytes with the microvasculature to improve our capabilities of establishing normally-functioning regenerated myocardium. In the preliminary studies of this proposal, we present data indicating that cardiomyocytes and endothelial cells retain the ability to assemble in a manner analogous to the pericyte-endothelial assembly and stabilization steps of vasculogenesis. Similarly, our preliminary data show that in 3D culture, differentiated endothelial cells form capillary structures, and cardiomyocytes attach to the outside of these capillary structures, allowing the endothelial cells to prevent cardiomyocyteapoptosis. Here we propose three Aims investigating how cardiomyocyte-endothelial interactions may play a crucial role in re-establishing myocardial architecture.
Aim 1. To determine mechanisms used by endothelial cells to improve viability of nearby or adjacent cardiomyocytes.
Aim 2. To demonstrate in vivo that adjacent endothelial cells improve viability, growth, and maturation of cardiomyocytes, and to determine the mechanisms for these benefits.
Aim 3. To determine if endothelial cells can promote the development of new, alpha-Myosin Heavy Chain-positive mature cardiomyocytes from alpha-Myosin Heavy Chain-negative myocyte precursorcells, using genetic fate-mapping in mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL081404-03S1
Application #
7491393
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Evans, Frank
Project Start
2005-09-01
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$105,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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