An intact renin-angiotensin system is not obligate for the development of load-induced cardiac hypertrophy in the adult, although ANG II plays an important role in myocardial remodeling. The response of the fetal heart to increased load and the role of the renin-angiotensin system in cardiac growth are poorly understood. In species like the human and sheep, most cardiomyocytes are terminally differentiated at birth, with postnatal growth of the heart occurring by hypertrophy and not by increasing cell number. Thus factors affecting the total number of myocytes present within the myocardium need to be identified. Intrauterine events that accelerate the rate of terminal differentiation of cardiomyocytes or increases the rate of cell death (apoptosis) will lead to a reduction in the total cardiomyocyte number. This proposal is designed to investigate in normal and pathological states (chronic fetal anemia induced volume overload) the role of angiotensin II in regulating growth, maturation and proliferation of cardiac myocytes during two stages of fetal development. Specifically, we intend to use a chronically-catheterized fetal sheep model to investigate (1) mechanisms regulating fetal cardiomyocyte hypertrophy, hyperplasia and apoptosis in responses to increased cardiac load in vivo;(2) the differential effects of selective angiotensin II receptor blockade on these responses and, (3) whether these interventions produce permanent alterations in cardiac morphology and function. Adaptive changes in cardiomyocyte growth, maturation and proliferation in utero could produce alterations in cardiac morphology and function that may ultimately program the heart for cardiovascular disease and ventricular function in adult life.
|Sandgren, Jeremy; Scholz, Thomas D; Segar, Jeffrey L (2015) ANG II modulation of cardiac growth and remodeling in immature fetal sheep. Am J Physiol Regul Integr Comp Physiol 308:R965-72|
|Norris, Andrew W; Bahr, Timothy M; Scholz, Thomas D et al. (2014) Angiotensin II-induced cardiovascular load regulates cardiac remodeling and related gene expression in late-gestation fetal sheep. Pediatr Res 75:689-696|
|Segar, Jeffrey L; Volk, Ken A; Lipman, Michael H B et al. (2013) Thyroid hormone is required for growth adaptation to pressure load in the ovine fetal heart. Exp Physiol 98:722-33|
|Jonker, Sonnet S; Scholz, Thomas D; Segar, Jeffrey L (2011) Transfusion effects on cardiomyocyte growth and proliferation in fetal sheep after chronic anemia. Pediatr Res 69:485-90|
|Jonker, Sonnet S; Scholz, Thomas D; Segar, Jeffrey L (2011) The effect of adrenalectomy on the cardiac response to subacute fetal anemia. Can J Physiol Pharmacol 89:79-88|