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.
Highlights
Over the past decade, obesity and type 2 diabetes (T2D) have reached epidemic levels worldwide, becoming one of the most challenging health problems in the 21st century (Tabish, 2007; Zheng et al, 2018)
The Insulin sensitivity index (ISI) was significantly lower in diabetic groups, regardless of sex, indicating that insulin signaling may be impaired in diabetic groups of both sexes
Our data suggest that decreased insulin sensitivity, possibly via pAkt-dependent signaling and enhanced oxidative stress, may contribute to the elevated contractile responses in aorta of this model of T2D, regardless of sex
Summary
Obesity and type 2 diabetes (T2D) have reached epidemic levels worldwide, becoming one of the most challenging health problems in the 21st century (Tabish, 2007; Zheng et al, 2018). Cardiovascular diseases (CVDs) are one of the primary causes of morbidity and mortality in patients with diabetes (Brunner et al, 2005). Premenopausal women have a lower incidence of CVD when compared with agematched men (Barrett-Connor, 1994). Premenopausal women with diabetes lose the sex-based cardiovascular protection and experience a higher relative risk of CVD compared to diabetic men (Steinberg et al, 2000). It has been established that hyperglycemia and diabetes affect female and male vascular beds differently. We previously reported sex differences in the development of vascular dysfunction in arteries of streptozotocin-induced type 1 diabetic rats (Zhang et al, 2012; Han et al, 2016). The pathophysiology of vascular dysfunction in T2D is likely to differ from that in type 1 diabetes
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