Sex Chromosome Complement Contributes to Sex Differences in Bradycardic Baroreflex Response

Abstract

Abstract-To investigate whether sex chromosome complement modulates bradycardic baroreflex response and contributes to the angiotensin II-bradycardic baroreflex sex differences, we used the four core genotype mouse model in which the effect of gonadal sex and sex chromosome complement is dissociated, allowing comparisons of sexually dimorphic traits among XX and XY females, as well as in XX and XY males. In conscious gonadectomized (GDX) MF1 transgenic mice we evaluated baroreflex regulation of heart rate in response to changes in blood pressure evoked by phenylephrine (1 mg/mL), angiotensin II (100 g/mL), and sodium nitroprusside (1 mg/mL). The administration of phenylephrine in GDX-XY females resulted in a significantly lower baroreflex response when compared with the other genotypes (in beats ⅐ min Ϫ1 ⅐ mm Hg Ϫ1 [slopes of regression lines for GDX-XY females Ϫ3.56Ϯ0.37 versus Ϫ6.06Ϯ0.38, Ϫ6.37Ϯ0.54 and Ϫ6.70Ϯ0.34 for GDX-XY male, GDX-XX female, and GDX-XX male mice, respectively]) {F(1,19)ϭ9.63; PϽ0.01}. In addition, in both GDX-XY males and females, the angiotensin II-bradycardic baroreflex response was attenuated when compared with heart rate changes in GDX-XX male and female mice (in beats ⅐ min Ϫ1 ⅐ mm Hg Ϫ1 [slopes of regression lines: Ϫ2.83Ϯ0.28 versus Ϫ5.76Ϯ0.26 in GDX-XY and GDX-XX mice, respectively]) {F(1,19)ϭ13.91; PϽ0.005}. In contrast, reflex tachycardic responses to sodium nitroprusside were comparable in all of the genotypes. These data support the hypothesis that sex chromosome complement modulates reflex inhibition of heart rate to phenylephrine and angiotensin II. Elucidating the foundational sources of sexually dimorphic traits in the regulation of baroreceptor reflex may enable the design of more appropriate sex-tailored therapeutic treatments in the future.

X chromosome regulation: diverse patterns in development, tissues and disease

“…One such model — the four core genotype (4CG), in which XY and XX males, and XX and XY females are produced — has clearly shown that both the sex chromosome complement and gender have a role in phenotypic sex-specific differences 89 . For example, the number of X chromosomes can influence adiposity and cardiovascular sexual dimorphisms 90,91 . Using the 4CG mouse model, global gene expression differences that originate from the sex chromosomes have been shown to influence the entire genome, which suggests genome-wide effects 92 .…”

Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities

“…Several cardio-metabolic processes have also been shown to be influenced by sex chromosome complement, including stroke sensitivity with aging, cardiac ischemia/reperfusion injury, aortic aneurisms, hypertension, body fluid homeostasis and blood pressure regulation [48–53]. Multiple mechanisms could potentially contribute.…”

The end of gonad-centric sex determination in mammals

“…In studies of rodents, the sex difference is explained in part by gonadal hormones and partly by sex chromosome complement. Chronic or acute treatment of FCG mice with angiotensin II causes different changes in blood pressure and heart rate in XX vs. XY mice [65,66]. In the FCG model, such XX vs. XY differences are not explained by effects of Sry .…”