Estrogen Replacement Improves Mesenteric Arterial Relaxation and Insulin Signaling in Skeletal Muscle of UC Davis Pre-diabetic Rats
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Introduction
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 and insulin signaling in skeletal muscle (SKM) in presence or absence of estrogen at the early stage of diabetes.
Purpose
Here, we investigated the effects of 17β-estradiol (E2) replacement on mesenteric arterial (MA) function and SKM expression of molecules associated with insulin signaling in ovariectomized (ovex) UC Davis type 2 diabetes mellitus (UCD-T2DM) rats at the pre-diabetic stage.
Method
MA and SKM 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 (PD), ovex + placebo, (4) PD, ovex + E2. Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh, 10-8 to 10-5 M) in MA were measured before and after indomethacin (Indo, 10µM), a cyclooxygenase (COX) inhibitor; followed by addition of L-NAME (200µM), a nitric oxide synthase (NOS) inhibitor. The MA expression of estrogen receptors (ERs) and SKM expression of insulin signaling targets, and plasma E2 concentration were determined by Western blotting and ELISA assay.
Results
Here, we showed that E2 replacement significantly increased plasma estradiol concentration in both Ctrl and PD groups. ACh responses were similar in Ctrl groups, regardless of E2 replacement. ACh-induced relaxation was, however, markedly reduced in MA of placebo treated PD group compared with other groups. Treatment of ovariectomized PD 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 PD 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 PD group when compared with placebo treated group, indicating an enhanced role of NO in this group. 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. Analysis of ERs showed a higher expression of ER-beta only in MA of E2-treated ovariectomized PD group. Insulin receptor substrate (IRS-1) expression and phospho-AMP activated protein kinase-α (p-AMPK-α) were significantly reduced in SKM of Ovariectomized PD group relative to controls. Interestingly, the SKM expression of IRS-1 and p-AMPK-α were elevated in E2 treated ovariectomized PD group, suggesting a possible protective role for E2 in insulin signaling in pre-diabetic stage.
Significance
In conclusion, our data show that the impairment of EDV in pre-diabetic stage is likely mediated by a loss of EDHF. E2 treatment restores EDV in MA of Ovariectomized pre-diabetic group, possibly via elevated relative contribution of NO-mediated relaxation. We also show that estrogen may protect females from early consequences of hyperglycemia, possibly via improving the insulin signaling in SKM. Clearly, further studies are required to elucidate the underlying mechanisms for the effects of estrogen on vascular and insulin signaling in pre-diabetic stage.
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Estrogen Replacement Improves Mesenteric Arterial Relaxation and Insulin Signaling in Skeletal Muscle of UC Davis Pre-diabetic Rats
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 and insulin signaling in skeletal muscle (SKM) in presence or absence of estrogen at the early stage of diabetes.
