Potentiation of Acetylcholine-Induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats: Sex-Specific Responses

Abstract

Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. The objectives of this study were to examine whether there were (1) sex differences in aortic function and (2) alterations in the relative contribution of endothelium-derived relaxing factors in modulating aortic reactivity in UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine (ACh) was measured in aortic rings before and after exposure to pharmacological inhibitors. Relaxation responses to sodium nitroprusside were assessed in endothelium-denuded rings. Moreover, contractile responses to phenylephrine (PE) were measured before and after incubation of aortic rings with a nitric oxide synthase (NOS) inhibitor in the presence of indomethacin. Metabolic parameters and expression of molecules associated with vascular and insulin signaling as well as reactive oxygen species generation were determined. Diabetes slightly but significantly impaired EDV in response to ACh in aortas from females but potentiated the relaxation response in males. The potentiation of EDV in diabetic male aortas was accompanied by a traces of nitric oxide (NO)- and prostanoid-independent relaxation and elevated aortic expression of small- and intermediate conductance Ca2+-activated K+ channels in this group. The smooth muscle sensitivity to NO was not altered, whereas the responsiveness to PE was significantly enhanced in aortas of diabetic groups in both sexes. Endothelium-derived NO during smooth muscle contraction, as assessed by the potentiation of the response to PE after NOS inhibition, was reduced in aortas of diabetic rats regardless of sex. Accordingly, decreases in pAkt and peNOS were observed in aortas from diabetic rats in both sexes compared with controls. Our data suggest that a decrease in insulin sensitivity via pAkt-peNOS-dependent signaling and an increase in oxidative stress may contribute to the elevated contractile responses observed in diabetic aortas in both sexes. This study demonstrates that aortic function in UCD-T2DM rats is altered in both sexes. Here, we provide the first evidence of sexual dimorphism in aortic relaxation in UCD-T2DM rats.

Zucker Diabetic‐Sprague Dawley (ZDSD) rat: Type 2 diabetes translational research model

“…Mesenteric arterial vasodilatation was 24% less in male, but not in female, prediabetic UCD‐T2DM rats compared with age‐ and sex‐matched SD rats (Shaligram et al., 2020). In a subsequent ex vivo study looking at aortic endothelial function, it was found that acetylcholine‐induced vasodilatations were 17% greater in UCD‐T2DM males, but not females, compared with age‐ and sex‐matched SD rats (Akther et al., 2021). Both studies also reported changes to vascular muscle contractility, as evidenced by increased sensitivity and/or increased efficacy of the α 1 ‐adrenoceptor agonist phenylephrine (Akther et al., 2021; Shaligram et al., 2020).…”

“…In a subsequent ex vivo study looking at aortic endothelial function, it was found that acetylcholine‐induced vasodilatations were 17% greater in UCD‐T2DM males, but not females, compared with age‐ and sex‐matched SD rats (Akther et al., 2021). Both studies also reported changes to vascular muscle contractility, as evidenced by increased sensitivity and/or increased efficacy of the α 1 ‐adrenoceptor agonist phenylephrine (Akther et al., 2021; Shaligram et al., 2020). Together, the evidence suggests that the UCD‐T2DM rat, like the ZDSD rat, is useful for investigating the progressive vascular dysfunction in prediabetes to diabetes.…”

“…Elevated fasted plasma glucose >200 mg/dl lagged the detection of the elevated fed blood glucose levels by 2 months (Cummings et al., 2008). Levels of HbA1c >6% in combination with blood glucose concentrations have also been used as criteria to define diabetic groups for both male and females (Akther et al., 2021; Shaligram et al., 2020). Fasting HbA1c increased 2.25‐fold (from 4 to 9%) in UCD‐T2M rats fed regular diet from 2 to 6 months of age (Cummings, Stanhope, Graham, Baskin et al., 2010).…”

“…Studies conducted ex vivo with isolated blood vessels indicate that endothelial function with respect to vasodilator mechanisms is altered in the prediabetic and diabetic UCD‐T2DM rats (Akther et al., 2021; Shaligram et al., 2020). In female and male UCD‐T2DM rats, mesenteric arterial vasodilatation in response to the muscarinic agonist acetylcholine was reduced by 20 and 70%, respectively, in diabetic (6.7 to 8.5 weeks) compared with prediabetic groups (Shaligram et al., 2020).…”

17β-Estradiol Treatment Improves Acetylcholine-Induced Relaxation of Mesenteric Arteries in Ovariectomized UC Davis Type 2 Diabetes Mellitus Rats in Prediabetic State

“…The prevalence of CVD in premenopausal women is less than age-matched men, and female sex hormones, estrogen in particular, play a role in sex-specific cardiovascular protection in females (Barrett-Connor, 1994;Iorga et al, 2017). Several studies including ours suggest that diabetes affects male and female vascular beds differently (Witcher et al, 2010;Zhang et al, 2012;Lum-Naihe et al, 2017;Shaligram et al, 2020;Akther et al, 2021). Diabetes not only abrogates the female-specific cardiovascular protection, but also premenopausal women with diabetes experience higher CVD events than diabetic men (Peters et al, 2015;Castro, 2016), suggesting that hyperglycemia may overcome some of the beneficial effects of female sex hormones.…”