Neha Ali

 Introduction. Cardiovascular disease is the leading cause of mortality in men and women in the USA. However, the risk of developing CV disease increases among women following menopause⁵. With increasing life expectancy, women may spend more than three decades in this postmenopausal state, increasing the likelihood of metabolic diseases.^5,6 Estrogen has a protective role in CV health through regulation of vasculature, blood pressure via the kidney and the immune system, through the ER⍺, ERβ and GPR30 receptors.^3,5 Studies have established the importance of ER⍺ receptors in the subfornical organ as a key site where estrogen and angiotensin II interact.¹ Methods. A female mouse lacking ER⍺ receptors was bred with a male mouse expressing Nestin-Cre. One fourth of this progeny contains both the knockout of the ER⍺ receptor and the Cre recombinase needed for knockdown of the ER⍺ receptors in the subfornical organ of the brain. This group is referred to as Nestin-ER⍺^– mice. Another group of the progeny contained the knockdown of ER⍺ but lacked Cre recombinase needed for SFO selectivity, meaning there is a knockout of the nervous system. This group is referred to as the Con-E⍺^flox. These are two strains used within the study.¹ Next, a telemetry probe implantation in the carotid artery was performed in all mice to monitor BP. Osmotic pumps containing ANGII were then implanted subcutaneously on the backs of the mice. After 5 control days, the mice were infused with subcutaneous ANGII for 7 days. Values of BP and HR were recorded.¹ Results. Comparable baseline values of BP and HR were established for both groups. After a seven-day infusion of ANGII, MAP increased in both strains of mice. The increase in MAP with the Nestin-ER⍺^– mice was shown to be 22.6 ± 2.7 mmHg, while the Con-E⍺^flox strain increased by 11.4 ± 1.8 mmHg.¹ ANGII infusion did not result in a decrease of heart rate in either group. Conclusions. Through this study, it is established that the ER⍺ in the nervous system is needed for the protective effects of estrogen. The subfornical organ is a key site in which estrogen and the ER⍺ can interact with ANGII from the blood. This increased hypertensive effect of ANGII on the nervous system through the ER⍺ offers a site for further studies to understand how to better prevent CV disease exacerbation in postmenopausal women.

1. Xue B, Zhang Z, Beltz T, Guo F, Hay M, Johnson AK. Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice. Am J Physiol Regul Integr Comp Physiol 308:R507–R516, 2015.
2. Pollow DP, Romero-Aleshire MJ, Sanchez JN, Konhilas JP, Brooks HL. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause. Am J Physiol Regul Integr Comp Physiol 309: R1546 –R1552, 2015
3. Tazumi S, Yokota N, Kawakami M, Omoto S, Takamata A, Morimoto K. Effects of estrogen replacement on stress-induced cardiovascular responses via renin-angiotensin system in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 311: R898 –R905, 2016.
4. Yung LM, Wong WT, Tian XY, Leung FP, Yung LH, Chen ZY, Yao X, Lau CW, Huang Y. Inhibition of renin-angiotensin system reverses endothelial dysfunction and oxidative stress in estrogen deficient rats. PLoS One 6(3), 2011.
5. Deborah Clegg, Andrea L. Hevener, Kerrie L. Moreau, Eugenia Morselli, Alfredo Criollo, Rachael E. Van Pelt, Victoria J. Vieira-Potter. Sex Hormones and Cardiometabolic Health: Role of Estrogen and Estrogen Receptors. Endocrinology, 158(5):1095–1105, May 2017.
6. G. M. C. Rosano, I. Spoletini & C. Vitale. Cardiovascular disease in women, is it different to men? The role of sex hormones. Climacteric 20(2): 125-128, 2017.