One (1) 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 an intricate network of capillaries, with each myocyte next to at least 1 capillary, and endothelial-cardiomyocyte signaling in myocardium regulates not only development of the myocardium, but also myocyte function 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 of myocytes 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 cardiomyocyte apoptosis. Here we propose 3 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 precursor cells, 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 #
1R01HL081404-01
Application #
6955698
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
2005-09-01
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$423,807
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Segers, Vincent F M; Lee, Richard T (2010) Protein therapeutics for cardiac regeneration after myocardial infarction. J Cardiovasc Transl Res 3:469-77
Huang, Hayden; Macgillivray, Catherine; Kwon, Hyuk-Sang et al. (2009) Three-dimensional cardiac architecture determined by two-photon microtomy. J Biomed Opt 14:044029
Loffredo, Francesco; Lee, Richard T (2008) Therapeutic vasculogenesis: it takes two. Circ Res 103:128-30
Patwari, Parth; Lee, Richard T (2008) Mechanical control of tissue morphogenesis. Circ Res 103:234-43
Lammerding, Jan; Lee, Richard T (2007) Torn apart: membrane rupture in muscular dystrophies and associated cardiomyopathies. J Clin Invest 117:1749-52
Sanada, Shoji; Hakuno, Daihiko; Higgins, Luke J et al. (2007) IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest 117:1538-49
Hsieh, Patrick C H; Segers, Vincent F M; Davis, Michael E et al. (2007) Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13:970-4
Hsieh, Patrick C H; MacGillivray, Catherine; Gannon, Joseph et al. (2006) Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation 114:637-44
Huang, Hayden; Cruz, Francisco; Bazzoni, Gianfranco (2006) Junctional adhesion molecule-A regulates cell migration and resistance to shear stress. J Cell Physiol 209:122-30
Davis, Michael E; Hsieh, Patrick C H; Takahashi, Tomosaburo et al. (2006) Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc Natl Acad Sci U S A 103:8155-60

Showing the most recent 10 out of 11 publications