Purpose of Review Despite enhanced screening and therapeutic management, hypertension remains the most prevalent chronic disease in the United States and the leading cause of heart disease, chronic kidney disease, and stroke in both men and women. It is widely accepted that hypertension is a pro-inflammatory disease and that the immune system plays a vital role in mediating hypertensive outcomes and end organ damage. Despite known discrepancies in the risk of hypertension development between men and women, preclinical models of immune-mediated hypertension were historically developed solely in male animals, leading to a lack of sex-specific clinical practice guidelines or therapeutic targets. Recent Findings Following the NIH policy on the consideration of sex as a biological variable in 2015, significant advancements have been made into sex-specific disease mechanisms in inflammation and hypertension. Summary This review article serves to critically evaluate recent advancements in the field of sex-specific immune-mediated hypertension.

Although it is known that the prevalence and severity of hypertension increases in women after menopause, the contribution of T cells to this process has not been explored. Although the immune system is both necessary and required for the development of angiotensin II (ANG II) hypertension in men, we have demonstrated that premenopausal women are protected from T cell-mediated hypertension. The goal of the current study was to test the hypotheses that 1) female protection against T cell-mediated ANG II hypertension is eliminated following progression into menopause and 2) T regulatory cells (Tregs) provide premenopausal protection against ANG II-induced hypertension. Menopause was induced in Rag-1−/− mice (via 4-vinylcyclohexene diepoxide), and all mice received a 14-day ANG II infusion. Donor CD3+ T cells were adoptively transferred 3 wk before ANG II infusion. In the absence of T cells, systolic blood pressure responses to ANG II were similar to those seen in premenopausal mice (Δ12 mmHg). After adoptive transfer of T cells, ANG II significantly increased systolic blood pressure in postmenopausal females (Δ28 mmHg). A significant increase in F4/80 positive renal macrophages, an increase in renal inflammatory gene expression, along with a reduction in renal expression of mannose receptor C-type 1, a marker for M2 macrophages, accompanied the increase in systolic blood pressure (SBP). Flow cytometric analysis identified that Tregs were significantly decreased in the spleen and kidneys of Rag-1−/− menopausal mice versus premenopausal females, following ANG II infusion. In a validation study, an anti-CD25 antibody was used to deplete Tregs in premenopausal mice, which induced a significant increase in SBP. These results demonstrate that premenopausal protection against T cell-mediated ANG II hypertension is eliminated once females enter menopause, suggesting that a change in hormonal status upregulates macrophage-induced proinflammatory and T cell-dependent responses. Furthermore, we are the first to report that the presence of Tregs are required to suppress ANG II hypertension in premenopausal females. NEW & NOTEWORTHY Whether progression into menopause eliminated female protection against T cell-mediated hypertension was examined. Menopausal mice without T cells remained protected against angiotensin II (ANG II) hypertension; however, in the presence of T cells, blood pressure responses to ANG II increased significantly in menopause. Underlying mechanisms examined were anti-inflammatory protection provided by T regulatory cells in premenopausal females and renal inflammatory processes involving macrophage infiltration and cytokine activation.

Premenopausal females are protected from Angiotensin II (Ang II)-induced hypertension following the adoptive transfer of T cells from normotensive donors. For the present study, we hypothesized that the transfer of hypertensive T cells (HT) or splenocytes (HS) from hypertensive donors would eliminate premenopausal protection from hypertension. Premenopausal Rag-1-/- females received either normotensive (NT) or hypertensive cells, three weeks prior to Ang II infusion (14 days, 490 ng/kg/min). Contrary to our hypothesis, no increase in Ang II-induced blood pressure was observed in the NT/Ang or HT/Ang groups. Flow cytometry demonstrated that renal FoxP3+ T regulatory cells were significantly decreased and IHC showed an increase in renal F4/80+ macrophages in HT/Ang, suggesting a shift in the renal inflammatory environment despite no change in blood pressure. Renal mRNA expression of MCP-1, Endothelin-1, GPER-1 were significantly decreased in HT/Ang. The adoptive transfer of hypertensive splenocytes prior to Ang II infusion (HS/Ang) eliminated premenopausal protection from hypertension and significantly decreased splenic FoxP3+ T regulatory cells compared to females receiving normotensive splenocytes (NS/Ang). Expression of MIP-1a/CCL3, a potent macrophage chemokine was elevated in HS/Ang, however no increase in renal macrophage infiltration occurred. Together, these data show that in premenopausal females T cells from hypertensive donors are not sufficient to induce a robust Ang II mediated hypertension, in contrast, transfer of hypertensive splenocytes (consisting of T/B lymphocytes, dendritic cells, macrophages) is sufficient. Further work is needed to understand how innate and adaptive immune cells and estrogen signaling coordinate to cause differential hypertensive outcomes in premenopausal females.

T cells are required for the development of hypertension in male and postmenopausal female mice while premenopausal females are protected from T cell mediated hypertension. To better understand sex differences in immune-cell mediated hypertensive responses, we sought to determine if there were any significant differences in the immune cell profiles of premenopausal female (F), VCD-treated postmenopausal female (PMF), and male (M) mice. Spleens were collected from all mice and processed for flow cytometric analysis of T cell populations (n=8/group). Analysis of splenic T cell populations revealed no significant difference in the frequency of CD3+ or CD4+ T cells between groups (CD3+: F 33.4%, PMF 30.3%, M 30.2% of total lymphocytes, CD4+: F 64.8%, PMF 70.7%, M 67.5% of CD3+ cells). However, postmenopausal females had a significantly lower frequency of splenic CD8+ T cells compared to both males and premenopausal females (CD8+: F 27.9%, PMF 19.5%*, M 25.3% of CD3+ cells *p<0.05 vs M and F). Additionally, premenopausal females displayed significantly increased expression of the memory marker CD44 and the anti-inflammatory marker CTLA-4 on CD4+ cells compared to both males and postmenopausal females (MFI CD44: F 334.8*, PMF 269.4, M 280.4, MFI CTLA-4: F 100.7*, PMF 80.9, M 86.8 *p<0.01 vs M and PMF). Additional flow cytometric staining was performed to evaluate sex differences in splenic Antigen Presenting Cell (APC) populations (n=8/group). The frequency of CD11b+ APCs, thought to primarily represent macrophage populations, were significantly reduced in postmenopausal females compared to premenopausal females but there was no significant difference from males (CD11b +: F 14.6%, PMF 11.8%*, M 12.9% of monocytes *p<0.05 vs F). Additionally, CD11c+ dendritic cell populations were found to be significantly reduced in postmenopausal females compared to both males and premenopausal females (CD11c+: F 4.1%, PMF 2.8%*, M 3.9% of all monocytes *p<0.01 vs M and F). Taken together, these results indicate a significant difference in the baseline immune environment between male, premenopausal female and postmenopausal females which likely contribute to sex-differences in susceptibility to immune-mediated hypertension.

The diagnosis of previable preterm pre-labor rupture of membranes (PROM) is known to be associated with poor outcomes for both the mother and the fetus. Following previable preterm PROM, patients are generally offered either active management through the termination of the pregnancy or expectant management to increase the chances of fetal survival. It is difficult to counsel patients because there is a lack of data directly comparing maternal outcomes following active vs. expectant management. Using the data in the current literature, the goal of the present meta-analysis was to determine if there were any differences in terms of maternal risks when active versus elective management was chosen. PubMed, Google Scholar, EMBASE, and Scopus were searched. We found four studies accounting for a total of 506 patients. The risk ratio (RR) of chorioamnionitis in active vs. expectant management was 0.30 (with a 95% confidence interval, CI, of 0.09–1.02). The heterogeneity of the study results was 81% (I2). A sub–analysis of two included studies revealed an RR of postpartum hemorrhage in active vs. expectant management of 0.75 (95% CI 0.27–2.07) and an RR of maternal sepsis of 0.23 (95% CI 0.04–1.28). The heterogeneity of the study results for this sub-analysis was 68% (I2) for postpartum hemorrhage and 0% (I2) for maternal sepsis. Overall, there was no statistically significant difference in the risk of chorioamnionitis, postpartum hemorrhage, or maternal sepsis when active management was chosen over expectant management in previable preterm PROM at <24 weeks. The scarcity and the high heterogeneity of the available data likely contributed to the lack of statistical significance and calls for further work directly comparing maternal outcomes following active vs. expectant management.