Project I will study the role of adenosine in coordinating fetal coronary vascular growth and myocyte function during conditions of hypoxemia in the heart, as well as the long-term consequences of altered adenosine signaling in fetal life upon cardiac function in the adult. Studies using a model of fetal anemia to study fetal hypoxemia have shown that fetal adaptations for survival include a 30% increase in heart to body weight ratio, a 50% increase in stroke volume and cardiac output, a 6-fold increase in coronary blood flow and a doubling of coronary conductance with preservation of coronary reserve. This occurs in the face of a fall in fetal systemic arterial blood pressure and vascular resistance. Changes include an increase in myocardial HIF-1a and VEGF, and an increase in cardiac capillary volume density in both ventricles. Ventricular remodeling occurs with both myocyte hyperplasia and hypertrophy as eccentric hypertrophy normalizes wall tension. The vascular remodeling changes found in the fetus persist in the adult, and lead to greater myocardial damage following ischemia/reperfusion. A critical link between fetal environment and adult disease that is missing is the step that coordinates fetal myocyte and vascular growth and function.
Aim 1 will test the hypothesis that intracellular adenosine signaling regulates fetal coronary vascular growth and cardiomyocyte function in fetal hypoxemia.
In Aim 2, we will study the in vivo and in vitro role of intracellular MAP kinase (also called extracellular signal-regulated kinase, or ERK) signaling on adenosine-stimulated fetal coronary growth and myocardial function.
In Aim 3 we will determine the long-term consequences of either reduced or increased fetal adenosine receptor signaling upon coronary conductance and myocardial function in adulthood with the use of adenosine receptor specific agonists/antagonists.
Decreases in oxygen delivery during fetal life alter coronary vascular growth as well as myocyte differentiation for life. The Aims of this project are designed to improve our understanding of the mechanisms that coordinate vascular and myocyte function during fetal life and the subsequent effects upon adult cardiac function. Completion of this project will provide new knowledge for the optimal management of hypoxemic pregnancies.
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