Prenatal Testosterone Induces Sex-Specific Dysfunction in Endothelium-Dependent Relaxation Pathways in Adult Male and Female Rats1

Abstract

Prenatal testosterone (T) exposure impacts postnatal cardiovascular function, leading to increases in blood pressure with associated decreased endothelium-dependent vascular relaxation in adult females. Endothelial function in males is not known. Furthermore, which of the endothelial pathways contributes to endothelial dysfunction and if there exists sex differences are not known. The objective of this study was to characterize the relative contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to the impaired endothelium-dependent vasodilation in prenatal T-exposed adult males and females. Offspring of pregnant rats treated with T propionate or its vehicle were examined. Telemetric blood pressure levels and endothelium-dependent vascular reactivity were assessed with wire myography. Levels of nitric oxide synthase (NOS3) and Kcnn3 and Kcnn4 channel expression were examined in mesenteric arteries. Mean arterial pressure was significantly higher in T males and females than in controls. Endothelium-dependent acetylcholine relaxation was significantly lower in both T males and females. EDHF-mediated relaxation was specifically blunted in T males (Emax = 48.64% ± 3.73%) compared to that in control males (Emax = 81.71% ± 3.18%); however, NO-mediated relaxation was specifically impaired in T females (Emax = 36.01% ± 4.29%) compared with that in control females (Emax = 54.56% ± 6.37%). Relaxation to sodium nitroprusside and levcromakalim were unaffected with T-treatment. NOS3 protein was decreased in T females but not in T males. Kcnn3 expression was decreased in both T males and females compared to controls. These findings suggest that prenatal T leads to an increase in blood pressure in the adult offspring, associated with blunting of endothelial cell-associated relaxation and that the effects are sex-specific: EDHF-related in males and NO-related in females.

Enalapril Normalizes Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxation in Mesenteric Artery of Adult Hypertensive Rats Prenatally Exposed to Testosterone1

“…The present study confirms our previous finding that prenatal T exposure induces hypertension and impairs the endothelial EDHF component of vasodilation in resistance arteries [17] and expands on it by demonstrating that this impairment is reversed by enalapril treatment. In addition, we have demonstrated that enalapril specifically restored the expression and function of the Kcnn3 channel in mesenteric arteries of prenatal T-exposed rats.…”

“…It is of importance to note that endothelial dysfunction is shown to be a common denominator to all types of hypertension regardless of its pathogenesis [15]. Decreased generation of EDHF, which is particularly critical in resistance arteries, has been shown to contribute to impaired endothelium-dependent vasodilation in genetic as well as developmentally programmed hypertension [16][17][18][19][20][21][22][23]. Recently, a reduced expression of Kcnn3 channel mRNA, but not Kcnn4, was observed in mesenteric arteries of rats programmed to develop hypertension following prenatal exposure to testosterone (T) [17].…”

Elevated androgen levels induce hyperinsulinemia through increase in Ins1 transcription in pancreatic beta cells in female rats†

“…DHT group rats were implanted with DHT pellets (7.5-mg, 90-d release) for 10 weeks, and control rats were implanted with matched placebo pellets. This dose and duration of DHT were selected to mimic 2-fold increases in androgen levels in PCOS females [21][22][23][24][25]. At the end of the 10 weeks experimental period, rats were subjected to glucose tolerance test and then sacrificed by CO 2 inhalation.…”

Correlation between Digit Length Ratios and Risk Factors Associated with Metabolic Syndrome

“…Interestingly, treatment of various animals prenatally with testosterone produces the metabolic as well as reproductive disorders associated with PCOS [2][3][4][5][6][7][8][9]. The metabolic defects associated with prenatal androgen exposure are not limited to females, but are also seen in males [2,10,11]. Likewise, hypertension and insulin resistance are not only associated with PCOS, but also with metabolic syndrome which impacts both males and females.…”