The Role Of T Cells In Postmenopausal Hypertension

Abstract

The rate and severity of hypertension are much lower in women than men of a similar age. However, the incidence of hypertension and its complications increase dramatically after menopause, matching and then surpassing that of age-matched males. While current anti-hypertensive therapeutics can improve blood pressure in males, they have proven to be less effective in postmenopausal women. Clinical trials in menopausal women utilizing hormone replacement therapy have also produced controversial results, thus other approaches are necessary to control blood pressure in women after menopause. Targeting the endothelin system can attenuate hypertension in male mice, and components of this system are known to be upregulated in females after menopause. Recent evidence in male mice also demonstrates that T lymphocytes promote the development of hypertension. However, research into the role of the endothelin and immune systems during hypertension in females is lacking, and is necessary to better understand how blood pressure regulation changes after menopause and identify novel targets for anti-hypertensive drug development. Therefore, we sought to determine how the progression to menopause in the novel VCD mouse model of menopause impacts the degree of angiotensin II (Ang II) hypertension and whether antagonizing the ET-1 system could attenuate hypertension in menopausal animals. We also hypothesized that prevention of T cell-mediated responses contributes to sex differences in hypertension and that the increased degree of hypertension after menopause requires T cells. To determine how the gradual progression to menopause in VCD-treated mice impacts hypertension, we infused Ang II into premenopausal and VCD-treated peri- and postmenopausal animals. Compared to premenopausal mice, Ang II-induced hypertensive responses were significantly increased after menopause, but were unchanged during the perimenopause transition. 17𝛽-estradiol replacement during perimenopause prevented the increased hypertensive response in menopausal animals, demonstrating that upregulation of hypertension in this model is driven by the loss of estrogen-induced protective actions. To test the hypothesis that ETA receptor-mediated signaling promotes postmenopausal hypertension, VCD-treated menopausal mice were administered either the ETA receptor antagonist ABT-627, 17𝛽-estradiol replacement, or vehicle. The increased hypertensive response in menopausal mice was equally prevented by either ETA receptor antagonism or 17𝛽-estradiol replacement, supporting the notion that ET-1-targetted drugs may improve blood pressure control in postmenopausal women. To address the hypothesis that prevention of T cell-mediated responses contributes to sex differences in hypertension, Ang II was infused into T cell-deficient male and premenopausal or VCD-treated menopausal female Rag-1^(-/-) mice with or without CD3⁺ T cell adoptive transfer. The results support this hypothesis, demonstrating that T cells promote the increased hypertensive response in males, and that the T cell-dependent response is prevented in premenopausal females, establishing sex differences in hypertension. After menopause, T cells are required for the increase in hypertension. To test the hypothesis that anti-inflammatory regulatory T cells are required for resistance against hypertension in premenopausal females, PC-61 was administered to deplete regulatory T cells during 14 days of Ang II infusion. We found that regulatory T cell depletion significantly increased the degree of Ang II hypertension, supporting a critical anti-hypertensive role for regulatory T cells in premenopausal female mice.