Sexual dimorphism in rat aortic endothelial function of streptozotocin-induced diabetes: Possible involvement of superoxide and nitric oxide production

Abstract

Little is known of the interactions between diabetes and sex on vascular function. The objectives of this study were to investigate whether there were sex differences in rat aortic endothelial function one week after the induction of streptozotocin (STZ)-diabetes, and to examine the potential roles of superoxide and nitric oxide (NO) in this sex-specific effect. Endothelium-dependent vasodilatation to acetylcholine (ACh) was measured in rat aortic rings before and after treatment with MnTMPyP (25 μM), a superoxide dismutase. Contractile responses to phenylephrine (PE) were generated before and after treatment with L-NAME (200 μM), a nitric oxide synthase (NOS) inhibitor. The mRNA expression of NADPH oxidase (Nox) and endothelial nitric oxide synthase (eNOS) were also determined. We demonstrated that 1) STZ-diabetes impaired endothelium-dependent vasodilatation to ACh to a greater extent in female than male aortae, 2) inhibition of superoxide enhanced sensitivity to ACh only in diabetic females, and 3) Nox1 and Nox4 mRNA expression was significantly elevated only in aortic tissue of diabetic females. Furthermore, incubation of aortic rings with L-NAME potentiated PE responses in all groups, but aortae from control females showed a greater potentiation of the PE response after NOS inhibition compared with others. STZ-diabetes reduced the extent of PE potentiation after L-NAME and the aortic eNOS mRNA expression in females to the same levels as seen in males. These data suggest that a decrease in NO, resulting from either decreased eNOS or elevated superoxide, may partially contribute to the predisposition of the female aorta to injury early in diabetes.

Sex-specific vascular responses of the rat aorta: effects of moderate term (intermediate stage) streptozotocin-induced diabetes

“…In the current study, we observed a greater impairment of EDV to ACh as well as bradykinin (another endothelium-dependent vasodilator, data not shown) in rat aortic rings of female rats than males, 8 weeks following the induction of diabetes. However, when compared with the observations in the 1-week study (Han et al 2014), the effect of 8-week STZ-induced D r a f t diabetes in blunting EDV in females was much greater than in males as assessed by bigger rightward shift of ACh response compared to that in the 1-week study (Han et al 2014). This may suggest that the extent of EDV impairment in female diabetic rat aorta is dependent on the duration of the diabetic state among other factors.…”

“…It is also known that there are sex differences in NO bioavailability and that females have higher levels of NO than males (Forte et al 1998;GlushkovskayaSemyachkina et al 2006;Sullivan et al 2010). When compared NO-dependent responses in intact aortic rings, both enhanced (Aloysius et al 2012;Gisclard et al 1988;Rahimian et al 1997) or no change (Han et al 2014;Hayashi et al 1992 Shimizu et al 1993). In line with previous reports (Fukao et al 1997;Han et al 2014;Keegan et al 1995;Pieper and Siebeneich 1997;Shimizu et al 1993;Zhang et al 2012) demonstrate a compromised EDV in different vascular beds in diabetes.…”

“…Here, we show that 8-week STZ-induced diabetes impairs EDV in rat aorta. We recently reported a sex difference in aortic endothelial function 1 week after the induction of STZ diabetes (Han et al 2014). In the current study, we observed a greater impairment of EDV to ACh as well as bradykinin (another endothelium-dependent vasodilator, data not shown) in rat aortic rings of female rats than males, 8 weeks following the induction of diabetes.…”

“…However, 8 weeks after the induction of diabetes (an intermediate stage) the extent of impairment was greater in females than in males (Zhang et al 2012). We also observed sex differences in the development of impaired EDV in rat aorta one week after streptozotocin (STZ)-diabetes was induced (Han et al 2014). Thus, we examined the role of sex on the development of abnormal aortic responses in female and male STZ diabetic rats after 8 weeks.…”

“…The use of this concentration of L-NAME was based on previous studies (Han et al 2014;Zhang et al 2012). A vehicle only (no drugs present) study was performed simultaneously in aortic rings from the same animal.…”