Since the number of myocytes is fixed near the time of birth in mammalian species including humans, heart growth in utero also determines the potential for subsequent growth in the neonate, youth, and even adult. Thus, small chambers caused by inflow or outflow obstruction in utero may be unable to grow adequately after birth. Likewise, adult responses to valvular or ischemic disease may be limited by events in utero. The mechanisms regulating cardiac growth and terminal differentiation in utero are incompletely understood. Ang II and hemodynamic load, systolic and diastolic, are putative key determinants of cardiac growth and differentiation in utero. Furthermore, Ang II is likely to be an important regulator of hemodynamic load in utero. Thus, angiotensin may have direct (receptor mediated) and indirect (load mediated) effects on cardiac growth and differentiation. it is the purpose of this proposal to separate these contributions and to understand the mechanisms involved. Chronically instrumented fetal sheep will be utilized in order that hemodynamic load and direct action of angiotensin can be controlled and their respective roles definitively defined. A systolic load will be placed on the left ventricle by aortic occluder. Angiotensin will be blocked with AT 1 or 2 antagonists. The effects of hemodynamic load with zero, baseline or increased Ang Ii local direct agonism present are determined. likewise, the effect of baseline, no, or increased Ang II local agonism will be assessed in unloaded animals. Cardiac growth and differentiation will be assessed by gross and microscopic mensuration and percent binucleation. Gene expression of RAS components will be used to assess myocyte maturation. The effect of angiotensin on MAP kinase pathway activation will be assessed to determine a mechanism for differentiation and proliferation. This project will provide definitive data regarding the role of Ang Ii in the regulation of fetal heart growth and thus is an integral part of this Program Project Grant.
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