Sex-specific immune modulation of primary hypertension

Abstract

It is well known that the onset of essential hypertension occurs earlier in men than women. Numerous studies have shown sex differences in the vasculature, kidney and sympathetic nervous system contribute to this sex difference in the development of hypertension. The immune system also contributes to the development of hypertension; however, sex differences in immune system modulation of blood pressure (BP) and the development of hypertension has only recently begun to be explored. Here we review findings on the effect of one's sex on the immune system and specifically how these effects impact BP and the development of primary hypertension. We also propose a hypothesis for why mechanisms underlying inflammation-induced hypertension are sex-specific. These studies underscore the value of and need for studying both sexes in the basic science exploration of the pathophysiology of hypertension as well as other diseases.

Keywords: Hypertension; Inflammation; Kidney; Sex differences; Subfornical organ; T-cells.

Figure 1

Effect of the sex of T cell subpopulations on MAP and HR responses to Ang II in the male Rag1^−/− host during Ang II infusion. Shown is MAP (A,C) and HR (B,D) as a function of time in Rag1^−/−-M (closed square; n=13/group) and in Rag1^−/−-M after adoptive transfer of CD4⁺ (A,B) (diamond; CD4^F→Rag1^−/−-M; n=11/group) or CD8⁺ (C,D) (hexagon; CD8^F→Rag1^−/−-M; n=11/group) T-cells isolated from female (open symbol) or male (closed symbol) WT mouse spleens.

Figure 2

CD3⁺ T-cell infiltration into the SFO of male Rag-1^−/− mice. Shown are photomicrographs of representative CD3⁺ immunohistochemical stained 30 micron sections from the SFO of a Rag-1^−/−-F (A, left), and a Rag-1^−/−-M (A, right) mouse following Ang II infusion. (B) Photomicrographs of representative CD3⁺ immunohistochemical stained 30 micron sections from the SFO of Rag-1^−/−-M after adoptive transfer of female CD3⁺ cells (C, left), or male CD3⁺ cells (C, right) following Ang II infusion.

Figure 3

Hypothesis of the 17β-estradiol inhibitory mechanism of T cell “priming” of SFO inflammatory pathways. 17β-Estradiol activation of ERs in the SFO (green pentagons) acts at multiple sites within the SFO to modulate Ang II-induced brain inflammation, T cell infiltration, microglia activation, increased sympathetic activity and BP. 17β-Estradiol: 1) inhibits AT₁R-mediated increases in intracellular calcium; 2) inhibits Ang II-induced ROS formation in the SFO and decreases microglia activation; 3) inhibits expression of CCL2 and blocks translocation of T-cells; and, 4) inhibits Ang IIinduced activation of SFO neurons, thereby ultimately preventing increases in sympathetic outflow and subsequent hypertension.