Angiotensin II (ANG II) increases fetal blood pressure and stimulates fetal heart growth; however little is known regarding its direct effects on cardiomyocytes in vivo. We sought to determine whether ANG II stimulates heart growth and cardiomyocyte hypertrophy and/or hyperplasia in utero in the immature fetal heart independent of the effects on cardiac afterload. In twin gestation fetal sheep at ~100 d gestation (term 145 d), one fetus received a chronic (6 days) infusion of ANG II alone (50 ug/kg/min) or ANG II plus nitroprusside (NTP) to attenuate the increase in blood pressure; non-instrumented twins served as controls. ANG II alone, but not ANG II + NTP resulted in a significant increase in heart mass (left and right ventricle + septum, corrected for body weight) compared to controls. ANG II but not ANG II+NTP also significantly increased cardiomyocyte area compared to control and increased the percentage of binucleated myocytes. ANG II with or without concomitant infusion of NTP increased cardiac PCNA expression, a marker of proliferation. Steady-state protein expression of terminal mitogen-activated protein kinases, cyclin B1, cyclin E1 and p21 were similar among groups. We conclude that in vivo, ANG II increases fetal cardiac mass via cardiomyocyte hypertrophy, differentiation and to a lesser extent hyperplasia. The effects of ANG II on hypertrophy appear dependent upon the increase in blood pressure (mechanical load) whereas effects on proliferation are load-independent.
- Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology