Effects of Estrogen Replacement on ACh-Induced Relaxation in Mesenteric Arteries of Prediabetic Ovariectomized Rats

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The risk of cardiovascular diseases (CVD) is lower in premenopausal women than in men, and this lower risk is related to the presumptive cardioprotective effects of female sex hormones, estrogen in particular. However, premenopausal women with diabetes not only lose this protection, they also experience a higher relative risk of CVD compared to diabetic men. Several lines of evidence suggest that endothelial dysfunction represents early steps in the development of vascular complications in diabetes, and hyperglycemia is the central initiating factor for those complications. Nonetheless, there is insufficient evidence to establish the timeline of the loss of this female-specific protection in premenopausal patients with diabetes. The objective of this study was to investigate the effects of 17?-estradiol (E2) on mesenteric arterial function in UC Davis type 2 diabetes mellitus (UCD-T2DM) rats at the prediabetic stage. Mesenteric arteries (MA) were obtained from four groups of ovariectomized (ovex) female rats implanted with a subcutaneous pellet for 45 days: (1) Control, ovex + placebo, (2) Control, ovex + E2 (1.5mg/pellet), (3) prediabetic, ovex + placebo, (4) prediabetic, ovex + E2 (1.5mg/pellet). Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh, 10?8 to 10?5 M) in phenylephrine pre-contracted mesenteric arterial rings were measured before and after indomethacin (Indo, 10?m), a cyclooxygenase (COX) inhibitor, followed by addition of L-NAME (200?M), a nitric oxide synthase (NOS) inhibitor. When Indo and L-NAME are administrated, the remaining EDV to ACh is referred to as the endothelium-dependent hyperpolarization factor (EDHF)-type relaxation. There were no significant differences in ACh- induced relaxation between placebo and E2 treated controls. However, the ACh responses in MA was markedly reduced in prediabetic treated with placebo. Treatment of prediabetic with E2 enhanced the ACh-induced relaxation compared with its respective placebo group. Blocking of both COX and NOS completely abolished the relaxation responses to ACh in prediabetic, regardless of E2 replacement, suggesting no contribution of EDHF-type relaxation in this group. The E2 replacement, however, increased the contribution of NO-mediated vasodilation in MA of prediabetic rats. When compared with prediabetic groups, the effect of L-NAME was much smaller in controls, specifically after E2 replacement, indicating an elevated contribution of EDHF-type relaxation in E2-treated control. These data show that EDV was impaired in ovex rats at prediabetic stage, possibly due to loss of EDHF. However, an intriguing observation of this study was that, at the pre-diabetic stage, estrogen treated ovex rats exhibited intact EDV, regardless of loss of EDHF. This may be due to elevated contribution of NO to EDV in this group. Additional studies are required to establish the role of estrogen replacement in diabetic stages. Support or Funding Information Supported by NHLBI This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.