Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: a shift in the relative importance of EDRFs

Abstract

Rahimian R. Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: a shift in the relative importance of EDRFs. Am J Physiol Heart Circ Physiol 303: H1183-H1198, 2012. First published September 14, 2012 doi:10.1152 doi:10. /ajpheart.00327.2012 studies suggest that diabetes affects male and female vascular beds differently. However, the mechanisms underlying the interaction of sex and diabetes remain to be investigated. This study investigates whether there are 1) sex differences in the development of abnormal vascular responses and 2) changes in the relative contributions of endothelium-derived relaxing factors in modulating vascular reactivity of mesenteric arteries taken from streptozotocin (STZ)-induced diabetic rats at early and intermediate stages of the disease (1 and 8 wk, respectively). We also investigated the mesenteric expression of the mRNAs for endothelial nitric oxide (NO) synthase (eNOS) and NADPH oxidase (Nox) in STZ-induced diabetes in both sexes. Vascular responses to acetylcholine (ACh) in mesenteric arterial rings precontracted with phenylephrine were measured before and after pretreatment with indomethacin (cyclooxygenase inhibitor), N -nitro-L-arginine methyl ester (NOS inhibitor), or barium chloride (Kir blocker) plus ouabain (Na ϩ -K ϩ -ATPase inhibitor). We demonstrated that ACh-induced relaxations were significantly impaired in mesenteric arteries from both male and female diabetic rats at 1 and 8 wk. However, at 8 wk the extent of impairment was significantly greater in diabetic females than diabetic males. Our data also showed that in females, the levels of eNOS, Nox2, and Nox4 mRNA expression and the relative importance of NO to the regulation of vascular reactivity were substantially enhanced, whereas the importance of endotheliumderived hyperpolarizing factor (EDHF) was significantly reduced at both 1 and 8 wk after the induction of diabetes. This study reveals the predisposition of female rat mesenteric arteries to vascular injury after the induction of diabetes may be due to a shift away from a putative EDHF, initially the major vasodilatory factor, toward a greater reliance on NO.sex; diabetes; mesenteric arteries; nitric oxide; endothelium-derived hyperpolarizing factor CARDIOVASCULAR DISEASES (CVDs) are the major causes of morbidity and mortality in patients with diabetes mellitus. Several reports including our recent studies (30,31,36) suggest that hyperglycemia and diabetes affect male and female vascular beds differently. Clinically, premenopausal women have a lower incidence of CVDs compared with age-matched men. However, premenopausal women with diabetes not only lose this sex-based cardiovascular protection but also have a higher risk of CVDs than men (4,20,71). Nonetheless, there is insufficient evidence to establish the mechanism(s) underlying the loss of this female-specific cardiovascular protection in premenopausal patients with diabetes.Endothelial dysfunction is an early sign of diabetic vascular diseases. Endothelial dysfuncti...

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

“…The data reveal profound differences in the effects of cardiometabolic risk factors on the components of endothelial dilation in females versus males. In males (Figure 4), in the absence of risk factors, both eNOS and EDH contribute to vasodilation, with NOS contributing a greater proportion of mesenteric vasodilatory function than EDH (Figure 4A and 4D), consistent with prior studies 14, 15. Exposure of male mice to obesity, with or without hyperlipidemia, resulted in profound impairment in eNOS‐mediated relaxation of resistance vessels.…”

“…Hydrogen peroxide (H 2 O 2 ) is an additional vasodilator that activates potassium channels to contribute to EDH 12, 13. Sex differences have been described in the relative contribution of these endothelium‐derived relaxing factors to resistance vessel function in rodent models 14, 15. However, how these components are modulated in resistance vessels in response to cardiometabolic risk factors and whether there are sex differences in those responses have not been directly investigated.…”

Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder

“…Moreover, EET was more effective in female mice than in male mice (33). Another study showed that the female hormone estrogen has anti-inflammatory effects (20) and increases the expression of EET (10).…”

“…In clinical characteristics, the ratio of HT and current smoking of men was significantly higher than that of women (73 vs. 54.5%, P ϭ (12) reported that the spasm group has a high ratio of men, smokers, and HT. Spasm is defined by the presence of epicardial vasodilation; herein, the definition of CMVD was completely different, but it is reported that men have more influence of NO than women in vascular tone (17,24,33). Thus it is possible that the factors of decreasing NO as HT and smoking are predicted as incidence of CMVD, especially in men.…”

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

“…A number of reports including our previous studies have shown that acute exposure of blood vessels to high glucose impairs EDV to ACh (Goel et al 2008;Goel et al 2007). Impaired EDV has been also reported in experimental models of diabetes (De Vriese et al 2000;Johnstone et al 1993;Zhang et al 2012). However, there are also reports demonstrating an enhanced EDV in diabetes (Bhardwaj and Moore 1988;Shen et al 2003), and alterations in EDV are dependent on the duration of the diabetic state (Clarkson et al 1996;Pieper 1999).…”