Y‐chromosome lineage determines cardiovascular organ T‐cell infiltration in the stroke‐prone spontaneously hypertensive rat

Abstract

The essential role of the Y chromosome in male sex determination has largely overshadowed the possibility that it may exert other biologic roles. Here, we show that Y-chromosome lineage is a strong determinant of perivascular and renal T-cell infiltration in the stroke-prone spontaneously hypertensive rat, which, in turn, may influence vascular function and blood pressure (BP). We also show, for the first time to our knowledge, that augmented perivascular T-cell levels can directly instigate vascular dysfunction, and that the production of reactive oxygen species that stimulate cyclo-oxygenase underlies this. We thus provide strong evidence for the consideration of Y-chromosome lineage in the diagnosis and treatment of male hypertension, and point to the modulation of cardiovascular organ T-cell infiltration as a possible mechanism that underpins Y- chromosome regulation of BP.-Khan, S. I., Andrews, K. L., Jackson, K. L., Memon, B., Jefferis, A.-M., Lee, M. K. S., Diep, H., Wei, Z., Drummond, G. R., Head, G. A., Jennings, G. L., Murphy, A. J., Vinh, A., Sampson, A. K., Chin-Dusting, J. P. F. Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.

Sex differences in preclinical models of hypertension

“…Consomic strains derived from WKY and SHRSP rats have shown an increase in T-cell infiltration in the SHRSP, which was ameliorated by the introduction of the WKY-derived Y chromosome [ 54 ]. Perivascular T-cell infiltration was not different in normal WKY compared to WKY containing a SHRSP-derived Y chromosome, however, the latter presented elevated renal T-cell infiltration which possibly promoted sodium retention and, consequently, increased blood pressure [ 54 ]. Cytokine release from these infiltrated cells is thought to contribute to ROS production in the vascular endothelium [ 55 ].…”

“…↑ BP [24] ↓ NO production ↑ proinflammatory cytokines and↓ GFR in males [25] Genetic hypertensive models SHR ↑BP ↑ proteinuria and ↓ GFR in males [28] ↑ NO bioavailability in females? [40] Sex hormones [28,29] SHR-derived Y chromosome loci [34,35] Increased vascular collagen accumulation in males [37] Altered NO signalling [40] Improved renal anti-inflammatory mechanism in females [42] SHRSP ↑BP ↑ stroke incidence [46] ↑ inflammation and ↑ kidney dysfunction in males [47,48] ↓ NO bioavailability in males [47] SHRSP-derived Y chromosome loci [49,50] ↑ inflammatory state in males [54,55] Impaired NO-induced relaxation in males [47] DSS rat ↑ BP ↑ kidney damage [61] Sex hormones [58,59,61] ↑ Sympathetic activation in males [57,60] and ↑ vasodilatory prostaglandins in females [60] Hormone-induced PCOS rodent models (EV)-induced PCOS rat model [83] ↑ BP compared to female controls [83] ↑ Sympathetic activity in PCOS females [83] Peripubertal testosterone exposure mouse model [84] ↑ BP and ↑ dyslipidaemia compared to female controls [84] Testosterone enanthate-induced rat model [85] ↑ BP compared to female controls [85] Oxidative stress dysregulation in PCOS females [85] adults whose blood pressure levels are up to 6% higher in men compared to women [79]. It is important to note that these marked differences diminish after menopause: women have an increase in blood pressure which peaks at >70 years-old when the prevalence of hypertension is highe...…”

Pan‐risk factor for a comprehensive cardiovascular health management

“…Sex differences in CVD risk may have originated from an interaction between the gene with androgen receptor located on the X chromosome and sex hormones that provide the basis for sex differences in cardiovascular regulatory mechanisms in the lifespan 8 . The Y chromosome is one of the strongest genetic determinants of coronary artery disease (CAD) 9,10 . Even in the presence of similar CVD risk factors for both men and women, compared with men, women suffer from CVD 7 to 10 years later, which has been largely ascribed to the protective effects of estrogen before menopause 11 .…”

“… 8 The Y chromosome is one of the strongest genetic determinants of coronary artery disease (CAD). 9 , 10 Even in the presence of similar CVD risk factors for both men and women, compared with men, women suffer from CVD 7 to 10 years later, which has been largely ascribed to the protective effects of estrogen before menopause. 11 The marked reduction in estrogen levels in and after menopause may explain the delayed clinical onset of CVD in women.…”

Y Chromosome, Hypertension and Cardiovascular Disease: Is Inflammation the Answer?

“…Given well-established sex differences in adaptive immunity and mounting evidence that Y chromosome haplogroup influences immunity to in turn mediate susceptibility to cardiovascular disease, we investigated whether Y-chromosome-dependent differences in BP in rodent were associated with Y-chromosome-dependent differences in T cell infiltration [36]. We have previously shown Y-chromosome-dependent differences in BP in consomic strains, with introgression of the SHRSP Y chromosome into the WKY background increasing BP and vice versa [26].…”