This proposal will employ quail (Aim 1) and mice (Aim 2-4) to address the overall hypothesis that the continuum of events required to form the hierarchy of the coronary vascular tree requires a complex interplay of cells and molecular signals which are temporally regulated. Experiments in Aim 1 will use in vitro (heart explants) and in ovo approaches to establish the specificity, interactions, and signaling of growth factors that regulate coronary vasculogenesis and angiogenesis during the stages preceding coronary artery formation.
Aim 2 will determine the harmonic interplay of growth factors that facilitate postnatal coronary artery growth by examining the assembly, growth and remodeling of the coronary arterial tree. Neutralizing antibodies to growth factors and soluble receptors will be used in Aims 1 and 2 in order to test hypotheses regarding the specific roles of growth factors in various components of the vasculogenic/angiogenic cascade.
Aim 3 will address the contribution of bone marrow-derived cells to coronary vessel formation during development. This novel aim tests the hypothesis that these cells are activated by specific growth factors and constitute a second source of precursor cells (the first being the epicardial, subepicardial region) that contribute to early postnatal formation of the coronary vasculature. Finally, Aim 4 addresses cyclic and static stretch, as key players in activating angiogenic growth factors and receptors of both cardiomyocytes and endothelial cells. Three unique features of these studies are that they 1) address the continuum of events constituting the development of the coronary tree and the growth factors which regulate these events, 2) are the first to address bone marrow-derived cells as contributors to the coronary vessels during development, and 3) explore stretch as a growth associated stimulus for myocardial vascularization. Since cardiac development depends on timely and adequate vascularization, an understanding of coronary vasculogenesis and angiogenesis will provide an important foundation for our understanding of cardiac defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075446-01A1
Application #
6821575
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
2004-07-01
Project End
2008-05-31
Budget Start
2004-07-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$368,750
Indirect Cost
Name
University of Iowa
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Tomanek, Robert J (2016) Developmental Progression of the Coronary Vasculature in Human Embryos and Fetuses. Anat Rec (Hoboken) 299:25-41
Tomanek, Robert J; Yu, Qing; Lo, Cecilia W (2015) Coronary anomalies in mice with congenital heart defects. Anat Rec (Hoboken) 298:408-17
Tomanek, Robert J; Christensen, Lance P; Simons, Michael et al. (2010) Embryonic coronary vasculogenesis and angiogenesis are regulated by interactions between multiple FGFs and VEGF and are influenced by mesenchymal stem cells. Dev Dyn 239:3182-91
Torry, Ronald J; Tomanek, Robert J; Zheng, Wei et al. (2009) Hypoxia increases placenta growth factor expression in human myocardium and cultured neonatal rat cardiomyocytes. J Heart Lung Transplant 28:183-90
Tomanek, Robert J; Hansen, Heidi K; Christensen, Lance P (2008) Temporally expressed PDGF and FGF-2 regulate embryonic coronary artery formation and growth. Arterioscler Thromb Vasc Biol 28:1237-43
Zheng, Wei; Christensen, Lance P; Tomanek, Robert J (2008) Differential effects of cyclic and static stretch on coronary microvascular endothelial cell receptors and vasculogenic/angiogenic responses. Am J Physiol Heart Circ Physiol 295:H794-800
Dedkov, Eduard I; Thomas, Mathew T; Sonka, Milan et al. (2007) Synectin/syndecan-4 regulate coronary arteriolar growth during development. Dev Dyn 236:2004-10
Awad, Ola; Dedkov, Eduard I; Jiao, Chunhua et al. (2006) Differential healing activities of CD34+ and CD14+ endothelial cell progenitors. Arterioscler Thromb Vasc Biol 26:758-64
Tomanek, Robert J; Ishii, Yasuo; Holifield, Jennifer S et al. (2006) VEGF family members regulate myocardial tubulogenesis and coronary artery formation in the embryo. Circ Res 98:947-53
Dedkov, Eduard I; Perloff, Joseph K; Tomanek, Robert J et al. (2006) The coronary microcirculation in cyanotic congenital heart disease. Circulation 114:196-200

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