Our group first showed that angiotensin-(1-7) [Ang-(1-7)] increases in the plasma and urine of normal pregnant women. In preeclamptic pregnant subjects we demonstrated a decrease of plasma Ang-(1-7) greater than that of Ang II. These initial findings provide a basis for an important physiological role for Ang-(1-7) in the course of pregnancy and in pregnancy-induced hypertension (PIH) where there may be a diminished influence of Ang-(1-7) to oppose the local tissue actions of Ang II. New data from our laboratory showed that Ang-(1-7) enhanced mesentery artery dilation in pregnancy and this was accompanied by increased kidney and urine levels of Ang-(1-7) in normal pregnant rats. Preliminary studies showed that urinary excretion of Ang-(1-7) was reduced in an animal model that resembles PIH. In addition, our recent discovery that angiotensin converting enzyme 2 (ACE2), a carboxypeptidase that exhibits high efficacy for Ang II metabolism to Ang-(1-7), is present in the kidney and uterus of pregnant rats, is localized to similar regions in kidney and uterus as Ang-(1-7), and is up-regulated in pregnancy suggests the hypothesis that increased expression of ACE2 leads to an enhanced formation of Ang-(1-7) during pregnancy. The hypothesis to be assessed in these studies is twofold: 1) that pregnancy is a model of overexpression of Ang-(1-7) resulting from increased expression of ACE2; 2) that the resulting hemodynamic profile (i.e the decreased peripheral resistance seen in normal pregnancy) is dependent upon up-regulation of ACE2 leading to enhanced formation of Ang-(1-7), whereas PIH (characterized by increased total peripheral resistance and uteroplacental ischemia) is due to unbridled pressor/ischemic actions of Ang-II as a consequence of a marked reduction of the formation and vasodepressor effects of Ang-(1-7).
The Specific Aims are: 1) to assess the evolutionary expression of Ang-(1-7) and ACE2 at early, mid and late gestation in normal and the reduced uterine perfusion pressure (RUPP) pregnant rats; 2) to determine the contribution of the ACE2 pathway to Ang-(1-7) formation at early, mid and late gestation in normal pregnant and RUPP pregnant rats; 3) to assess the systemic and regional hemodynamic role of Ang-(1-7) and ACE2 in normal and RUPP pregnant rats; and 4) to characterize the null ACE2-/- pregnant mouse by detertm'ning the impact of the loss of the gene on blood pressure regulation. The proposed research will establish a novel and significant new dimension to the contribution of the RAS in the physiology and pathology of pregnancy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
United States
Zip Code
Dell'Italia, Louis J; Collawn, James F; Ferrario, Carlos M (2018) Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling. Circ Res 122:319-336
Ahmad, Sarfaraz; Ferrario, Carlos M (2018) Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010-2018). Expert Opin Ther Pat 28:755-764
Wang, Hao; Sun, Xuming; Lin, Marina S et al. (2018) G protein-coupled estrogen receptor (GPER) deficiency induces cardiac remodeling through oxidative stress. Transl Res 199:39-51
Ahmad, Sarfaraz; Sun, Xuming; Lin, Marina et al. (2018) Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR. J Cell Physiol 233:3330-3342
Li, Tiankai; Zhang, Xiaowei; Cheng, Heng-Jie et al. (2018) Critical role of the chymase/angiotensin-(1-12) axis in modulating cardiomyocyte contractility. Int J Cardiol 264:137-144
Ola, Mohammad Shamsul; Alhomida, Abdullah S; Ferrario, Carlos M et al. (2017) Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy. Curr Med Chem 24:3104-3114
Ferrario, Carlos M; Mullick, Adam E (2017) Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res 125:57-71
Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
Alencar, Allan K; da Silva, Jaqueline S; Lin, Marina et al. (2017) Effect of Age, Estrogen Status, and Late-Life GPER Activation on Cardiac Structure and Function in the Fischer344√óBrown Norway Female Rat. J Gerontol A Biol Sci Med Sci 72:152-162
Guichard, Jason L; Rogowski, Michael; Agnetti, Giulio et al. (2017) Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure. Am J Physiol Heart Circ Physiol 313:H32-H45

Showing the most recent 10 out of 309 publications