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.
|Chattergoon, N N; Louey, S; Stork, P J et al. (2014) Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes. Am J Physiol Heart Circ Physiol 307:H1216-25|
|Rinkevich, Diana; Belcik, Todd; Gupta, Nandita C et al. (2013) Coronary autoregulation is abnormal in syndrome X: insights using myocardial contrast echocardiography. J Am Soc Echocardiogr 26:290-6|
|Thornburg, Kent L; Louey, Samantha (2013) Uteroplacental circulation and fetal vascular function and development. Curr Vasc Pharmacol 11:748-57|
|Anderson, Debra F; Jonker, Sonnet S; Louey, Samantha et al. (2013) Regulation of intramembranous absorption and amniotic fluid volume by constituents in fetal sheep urine. Am J Physiol Regul Integr Comp Physiol 305:R506-11|
|Fan, L; Lindsley, S R; Comstock, S M et al. (2013) Maternal high-fat diet impacts endothelial function in nonhuman primate offspring. Int J Obes (Lond) 37:254-62|
|Chattergoon, Natasha N; Giraud, George D; Louey, Samantha et al. (2012) Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J 26:397-408|
|Bernard, Leah S; Hashima, Jason N; Hohimer, A Roger et al. (2012) Myocardial performance and its acute response to angiotensin II infusion in fetal sheep adapted to chronic anemia. Reprod Sci 19:173-80|
|Back, Stephen A; Riddle, Art; Dean, Justin et al. (2012) The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359-70|
|Chattergoon, Natasha N; Louey, Samantha; Stork, Philip et al. (2012) Mid-gestation ovine cardiomyocytes are vulnerable to mitotic suppression by thyroid hormone. Reprod Sci 19:642-9|
|Thornburg, Kent; Jonker, Sonnet; O'Tierney, Perrie et al. (2011) Regulation of the cardiomyocyte population in the developing heart. Prog Biophys Mol Biol 106:289-99|
Showing the most recent 10 out of 67 publications