ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

Abstract

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. First published October 21, 2015 doi:10.1152/ajpregu.00170.2015.-Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg Ϫ1 ·min Ϫ1 ) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17␤-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17␤-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17␤-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause.aquaporin-2; glomerular hypertrophy; collecting duct; estrogen PREMENOPAUSAL FEMALES are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease incidence and severity (20). Similarly, resistance to ANG II-induced hypertension has been demonstrated in female rodents. Ovariectomy (the abrupt induction of menopause via the removal of gonads) removes this resistance to ANG II, resulting in a robust ANG II-induced hypertensive response (39). Pharmacological inhibition or genetic ablation of estrogen receptors also increases the hypertensive response to ANG II infusion, suggesting that the loss of 17␤-estradiol signaling during menopause is in part responsible for the shift in blood pressure regulation (40).R...

The VCD Mouse Model of Menopause and Perimenopause for the Study of Sex Differences in Cardiovascular Disease and the Metabolic Syndrome

“…However, this protection was lost after ovarian failure, as blood pressure increased significantly in VCD-treated menopausal mice. 17␤-Estradiol treatment prevented this increase in blood pressure (FIGURE 5D) (17). These results confirm the utility of the VCD model of menopause to study the mechanisms of hypertension in menopausal females and further demonstrate the vital role that female sex hormones play in regulating disease pathogenesis.…”

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…In particular, 17β‐estradiol strongly prevents lipid deposition in mouse models of atherosclerosis: apolipoprotein E–deficient6, 7 and low‐density lipoprotein receptor–deficient (LDLr −/− )8 mice. In addition, in several experimental models of hypertension, ovariectomy exacerbates, whereas estrogen replacement attenuates, the course of hypertension9, 10 and reduces arterial stiffening associated with hypertension or aging 11. 17β‐estradiol also increases basal nitric oxide (NO) production,12 accelerates reendothelialization,8, 13 and prevents postinjury medial as well as neointimal hyperplasia after vessel injury 14.…”

Glucose homeostasis in rats treated with 4-vinylcyclohexene diepoxide is not worsened by dexamethasone treatment

“…The vast majority of studies conducted with 4-VCD model sought to elucidate its mechanisms of action and the comprehension of the profile of ovary-derived hormones (e.g., concentrations and time-course fluctuations) [7][8][9][10][11][12][13][14][15]. There are few studies exposing these animals to a physiological challenge [16][17][18]. For instance, 4-VCD-treated mice under menopause become more responsive to the angiotensin II hypertensive effects, which do not happen during perimenopause [18].…”

“…There are few studies exposing these animals to a physiological challenge [16][17][18]. For instance, 4-VCD-treated mice under menopause become more responsive to the angiotensin II hypertensive effects, which do not happen during perimenopause [18]. Similarly, mice become glucose intolerant 26 weeks after 4-VCD administration [17].…”