ANIMAL MODELS FOR CARDIOVASCULAR DISEASE

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Growth and differentiation factors are known to play regulatory roles in the cardiovascular response to stress and injury, such as the hypertrophic response of cardiac and arterial smooth muscle to hypertension, the response of vascular endothelium and smooth muscle to injury after angioplasty, and also in the repair and protective responses of the heart and vasculature to ischemic attack. To study these responses at the whole animal level, we have genetically engineered mice in which two of these growth factors, transforming growth factor beta-1 (TGFbeta1) and basic fibroblast growth factor (FGF2) have been ablated or overexpressed, respectively. The TGFbeta1-deficient mouse displays impaired cardiac contractility, abnormal vascular smooth muscle cell (VSMC) growth, and poor platelet aggregation. Many of these phenotypes implicate abnormal Ca2+ handling as the molecular basis of the defects. The transgenic FGF2 mouse has impaired VSMC growth. To these animal resources we will add FGF2 knockout mice which are deficient in specific FGF2 isoforms thought to play differential functional roles in the cardiovascular system. Finally, we will continue to develop tissue-specific, or conditional, knockout schemes in order to ablate gene function only in specific tissues of the animal. With these animal models we will investigate i) the role of TGFbeta1 in regulating Ca2+ flux in cardiomyocytes, ii) the roles of TGFbeta1 and FGF2 in the development of cardiac hypertrophy and the resulting switch in muscle protein isoforms, iii) the regulatory role of TGFbeta1 in platelet function, iv) the protective roles of FGF2 and TGFbeta1 in ischemia- reperfusion injury, v) development of microvasculature, and vi) growth control in vascular smooth muscle and endothelium after de-endothelization. Physiological approaches at the whole animal, whole organ and isolated cell levels will include echo Doppler cardiography, work-performing and Langendorff whole heart preparations, isolated cardiac cell mechanics, Ca2+ transient measurements,a nd single ion channel recordings and VSMC and endothelial cell culture. Altered expression of factors that co-regulate cardiovascular functions with TGFbeta and FGF, and of downstream effectors of TGFbeta1 and FGFbeta1 and GGF2 will be measured. With these studies we will obtain more definitive information on the roles of growth factors in contractility, cardiac and VSMC hypertrophy, ischemia-reperfusion injury, neovascularization, arterial injury, and platelet dysfuncTIon.