Estrogen Replacement Improves Mesenteric Arterial Relaxation in UC Davis Pre-diabetic Rats: Possible Involvement of Estrogen Receptor Beta

The risk of cardiovascular diseases (CVD) is lower in premenopausal women compared to men, and this lower risk is related to the presumptive cardioprotective effects of female sex hormones, estrogen in particular. However, premenopausal women may lose this protection with the onset of menopause and/or when they become diabetic. Little is known about the vascular function in presence or absence of estrogen at the early stage of diabetes. The objective of this study was to investigate the effects of 17?-estradiol (E2) replacement on mesenteric arterial (MA) function in ovariectomized (ovex) UC Davis type 2 diabetes mellitus (UCD-T2DM) rats at the pre-diabetic stage. MA were obtained from four groups of ovex rats implanted with a subcutaneous pellet for 45 days: (1) Control (Ctrl), ovex + placebo, (2) Ctrl, ovex + E2 (1.5mg/pellet), (3) pre-diabetic, ovex + placebo, (4) pre-diabetic, ovex + E2. Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh, 10?8 to 10?5 M) in MA 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. The MA expression of estrogen receptors (ERs) and plasma E2 concentration were determined by Western blotting and ELISA assay, respectively. E2 treatment significantly increased plasma estradiol concentration in both Ctrl and Prediabetic groups. Analysis of ERs showed a higher expression of ER-beta only in E2-treated prediabetic group. ACh responses were similar in Ctrl groups, regardless of E2 replacement. ACh induced relaxation was, however, markedly reduced in MA of placebo treated pre-diabetic group compared with other groups. Treatment of pre-diabetic with E2 enhanced relaxation to the same level as those from Ctrl rats. Blocking of both COX and NOS completely abolished the relaxation responses to ACh in pre-diabetic groups, regardless of E2 replacement, indicating no contribution of EDHF-type relaxation in these groups. However, the added effect of L-NAME, in presence of Indo, in blocking ACh-mediated vasodilation was much more prominent in E2-treated prediabetic group when compared with placebo treated group, indicating an enhanced role of NO. On the other hand, both NO and EDHF remained important for EDV in Ctrl groups. Addition of L-NAME, however, caused a much smaller reduction of EDV in E2 treated than in placebo treated arteries, suggesting EDHF is the predominant mediator of mesenteric vasorelaxation in this groups. Here, we show that EDV is impaired at pre-diabetic stage, may be due to loss of EDHF. E2 treatment restores EDV in MA of pre-diabetic group, possibly via elevated contribution of NO-mediated relaxation by increased E2 signaling (via ER beta) in this group. The role of ER alpha remains to be investigated. Support or Funding Information Supported by NHLBI