Sex Specific Differences in a Lipodystrophy‐induced Hypertension Mouse Model

Abstract

Obesity rate is higher in women than in men and is more strongly associated with hypertension in extremely obese women. However, the relative contribution of the adipose tissue itself to blood pressure control and to anti‐hypertensive drug's efficacy is not completely understood and is often difficult to assess because of its inter‐ and intra‐variability within subject and within sex.In the present study, we used a lipodystrophy‐induced hypertension mouse model, adipose prorenin receptor (PRR) KO mice, to investigate sex differences in the relative contribution of adipose tissue to hypertension and to antihypertensive drug's efficacy. Autonomic nervous system inhibitors and AT1R blockers (ARBs) were used to investigate whether the elevation of blood pressure observed in adipose PRR KO male and female mice was driven by the same mechanism. The decrease of systolic blood pressure (SBP) induced by losartan, an AT1R blocker, was exacerbated in high fat (HF)‐fed adipose PRR KO female mice compared with control female mice but not in male mice (Delta SPB: CTL male, −7.9±1.5 mmHg; KO male, − 6.4±3.1 mmHg; CTL female, −5.3±1.9 mmHg; KO female, −14.2±0.9 mmHg). In contrast, the contribution of the autonomic nervous system, assessed via injections of propranolol, atropine and chlorisondamine, revealed that the tachychardic response was significantly greater in HF‐fed adipose PRR‐KO male mice compared with control, but not in female mice (Delta heart rate: CTL male, +114.2±12.1 bpm; KO male, +156.0±11.1 bpm; CTL female, +84.8±10.1 bpm; KO female, +89.8±21.3 bpm). Together, our data indicated that SBP elevation was primarily mediated by an AngII‐dependent mechanism in HF‐fed adipose PRR‐KO female mice whereas it was mainly driven by the para‐sympathetic nervous system in HF‐fed male adipose PRR‐KO mice. The present study also suggested that the presence of an expanded adipose tissue decreased the ability of female to respond to ARBs whereas it decreased the ability of male to respond to autonomic nervous system inhibitors. Interestingly, plasma sPRR, the soluble form of PRR, is higher in female than in obese male mice (CTL: Male: 2.8 ± 0.3 ng/ml; Female: 5.1 ± 0.5 ng/ml) and in HF‐fed adipose PRR KO female than in adipose PRR KO male mice (KO: Male: 7.1 ± 0.1 ng/ml; Female: 11.6 ± 2.4 ng/ml). Whether sPRR contributes to obesity‐hypertension and to the phenotype observed in adipose PRR‐KO mice through a sex specific mechanism is currently under investigation. Together our data support the importance of personalized medicine for antihypertensive treatment choices.Support or Funding InformationNational Institutes of Health Grants (R01‐HL‐130463), American Heart Association (13SDG17230008), National Institute of General Medical Sciences (P20‐GM103527), University of Kentucky, Center for Clinical and Translational Sciences (UL1TR000117)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.