The overall goal of this project is to determine the role of key growth factors, ventricular loading and growth on coronary vasculogenesis and angiogenesis. The proposed experiments will utilize hearts from both avian (chicken) and mammalian (rat) species.
Aim 1 is to determine the role of vascular endothelial growth factor (VEGF) in the regulation of specific events comprising coronary vascularization. The applicant will test the hypothesis that VEGF stimulates coronary vascularization during prenatal heart development by treating embryonic hearts with exogenous VEGF and it neutralizing antibodies. To test the hypothesis that hypoxia serves as a trigger for VEGF expression in the ventricle during prenatal heart development, the applicant will expose chicken embryos and embryonic rat hearts grafted in oculo to lowered O2.
Aim 2 is to determine the role of fibroblast growth factor (bFGF) in the regulation of specific events comprising coronary vascularization. To test the hypothesis that bFGF modulates vascularization at key time points during prenatal and postnatal heart development, embryonic and fetal hearts will be treated with bFGF and its neutralizing antibodies commencing at different stages of development. A second hypothesis is that unlike prenatal vascularization, late postnatal vascular growth can be stimulated in the absence of bFGF. In these studies thyroxine, which has been shown to stimulate coronary angiogenesis, will be administered to rats in combination with neutralizing antibodies for bFGF.
Aim 3 is to establish the influence of ventricular loading conditions and mass on specific events comprising coronary vascularization and will be explored in a chicken model of differential loading (left ventricular hypoplastic syndrome with hyperplastic right ventricle). The hypotheses that the onset and magnitude of vascular growth is regulated by the thickness of the ventricular wall and that the timing of the ingrowth of the coronary arteries is related to the acceleration or deceleration of ventricular microvascular growth will be tested. The final hypothesis is that VEGF expression is modulated by the extent of ventricular growth.
These aims are based on studies which will employ a variety of approaches including immunohistochemistry, histochemistry, in situ hybridization, image analysis, and Northern and Western analyses.
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