Sex-specific immune modulation of primary hypertension☆
Introduction
The onset of essential hypertension occurs earlier in men than women [1]. This BP sex difference in humans is also observed in experimental animal studies. Females have lower BP than males in numerous animal models of hypertension [2]. There has been an exponential growth over the last 10 years in our understanding of how multiple end organs including the kidney, peripheral vasculature and key brain regions involved in central regulation of sympathetic outflow contribute to sex differences in the development of hypertension and within the past couple of years, several excellent reviews have been written on this topic [3], [4], [5], [6], [7], [8], [9], [10], [11].
We and others have shown that the gonadal hormones play a key role in sex differences in the development of hypertension. Ovarian hormone deficiency due to premature ovarian failure [12] or menopause [13] is associated with an increased frequency of hypertension in women and numerous animal models of hypertension have shown that 17β-estradiol replacement prevents the rise in BP due to ovarian hormone depletion [2]. For example, we have shown that the increase in BP induced by ovariectomy in the angiotensin II (Ang II) [14]- and aldosterone [15]-infusion models of hypertension can be prevented by 17β-estradiol replacement. As in other models of hypertension, the young female spontaneously hypertensive rat (SHR) has lower BP than the male SHR. Once the female SHR reaches the age at which the estrous cycle ceases, the sex difference in BP disappears [5]. In contrast to many experimental models of hypertension, ovariectomy in the young SHR has no effect on BP, rather studies suggest testosterone plays a key role in the sex differences in BP in SHR. Reducing the levels of testosterone in the male SHR lowered BP [16]. Furthermore, congenic studies in which the SHR Y chromosome was replaced with a Y chromosome from the normotensive Wystar Kyoto (WKY) rat lowered BP as well as testosterone levels [17], [18]. The sex chromosomes can also contribute to sex differences in hypertension independently of the gonadal hormones. Using the four core genotype mouse model, which enables separation of sex chromosome effects from gonadal sex effects, we showed that BP was higher in gonadectomized XX mice compared to gonadectomized XY mice regardless of whether they were male (born with testes) or female (born with ovaries) [19]. Thus, the ovarian and testicular hormone status along with the sex chromosome complement and age of the animal all contribute to sex differences in the development of hypertension.
Recently, studies have demonstrated the immune system is activated in hypertension [20]. Inflammation and adaptive immunity in particular have emerged from both clinical and experimental data as important contributors to the development of hypertension [21], [22]. Inflammatory mechanisms in the kidney, peripheral vasculature, and central nervous system (CNS) all have been shown to be involved [23], [24], [25], [26], [27]; however, these studies were conducted primarily in males. Recent studies in females demonstrate sex-specific modulation of the immune system in hypertension. The focus of this review is to examine our current knowledge of the impact of one’s sex on immune modulation of BP and the development of the primary cause of hypertension, namely, essential hypertension. Immune modulation of other causes of hypertension such as pulmonary hypertension and preeclampsia are beyond the scope of this review. We also propose a new hypothesis regarding the mechanisms by which the sex chromosomes and gonadal hormones regulate inflammation-induced hypertension. Identification of the cellular mechanisms underlying these robust sex differences in BP may lead to sex-specific preventive strategies and therapeutics that ultimately result in reductions in the incidence of hypertension, delays in the onset of this disease and improved treatments for high blood pressure in both men and women.
Section snippets
Animals
Rag-1−/− and wild type (WT) mice on the C57BL/6 background were purchased from Jackson Labs. All methods were approved by the Georgetown University and the University of Arizona Animal Care and Use Committees.
T-cell isolations
Mature CD3+ T-cells were isolated from the spleens of male or female WT mice using Pan T-cell isolation kits (Miltenyi) and negative magnetic sorting for CD3+ isolation. The CD4+ and CD8+ T-cell subpopulations were then isolated by flow cytometry, as described previously [28].
Adoptive transfer
Both male and
The role of immune system in sex differences in the development of hypertension
One of the earliest studies implicating a role for the immune system in hypertension was performed by Grollman and colleagues in 1967. They demonstrated that hypertension could be induced in a normal male rat by transplanting this animal with lymph cells from the renal infarction rat model of hypertension [29]. Blood pressure was also shown to be increased in a normal rat by adoptive transfer of splenocytes isolated from a male rat made hypertensive by deoxycorticosterone acetate and sodium
The role of the kidney and vasculature in sex-specific T cell regulation of blood pressure
There is a growing body of evidence suggesting that T-cell infiltration into end organs is an important contributor to the pathology of hypertension and progression of the disease in males [20]. The initial studies by Guzik et al. [23] showed that Ang II infusion in [male] WT mice increased the expression of the chemokine receptor CCR5 and the hyaluronan receptor CD44 in circulating CD4+ lymphocytes and CCR5-ligand and RANTES in vascular tissue. Infiltration of both CD4+ and CD8+ T-cell
The role of the brain in sex-specific T-cell modulation of blood pressure
A number of studies suggest sex hormones defend the brain against pro-inflammatory processes and stimulate cell survival by activating anti-apoptotic pathways, decreasing reactive oxygen species (ROS) production and reducing glutamate excitotoxicity [44], [45]. Both astrocytes and the brain resident macrophage, microglia, express the two estrogen receptor (ER) subtypes (ERα and ERβ). Furthermore, 17β-estradiol actions on these cells contributes to the sex differences in brain inflammatory
Concluding remarks
In summary, there are significant sex differences in the role of the adaptive immune system in the modulation of BP and the development of essential hypertension. These sex differences may explain why males are more susceptible to hypertension than ovarian hormone replete females. The immune system mechanisms that result in hypertension in males are not extrapolatable to females. The studies reviewed above suggest that multiple factors contribute to these sex differences in immune modulation of
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This work was supported by NIH grants to K.S. (AG/HL-19291, AG-039779 & AG-16902).