Razan Md Rahatullah, Akther Farjana, Islam Rifat A, Graham James L, Stanhope Kimber L, Havel Peter J, Rahimian Roshanak
Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, United States.
Department of Molecular Biosciences, School of Veterinary Medicine, Department of Nutrition, University of California, Davis, Davis, CA, United States.
Front Physiol. 2022 Jun 17;13:900813. doi: 10.3389/fphys.2022.900813. eCollection 2022.
We recently reported sex differences in mesenteric arterial function of the UC Davis type-2 diabetes mellitus (UCD-T2DM) rats as early as the prediabetic state. We reported that mesenteric arteries (MA) from prediabetic male rats exhibited a greater impairment compared to that in prediabetic females. However, when females became diabetic, they exhibited a greater vascular dysfunction than males. Thus, the aim of this study was to investigate whether the female sex hormone, estrogen preserves mesenteric arterial vasorelaxation in UCD-T2DM female rats at an early prediabetic state. Age-matched female Sprague Dawley and prediabetic (PD) UCD-T2DM rats were ovariectomized (OVX) and subcutaneously implanted with either placebo or 17β-estradiol (E 1.5 mg) pellets for 45 days. We assessed the contribution of endothelium-derived relaxing factors (EDRF) to acetylcholine (ACh)-induced vasorelaxation, using pharmacological inhibitors. Responses to sodium nitroprusside (SNP) and phenylephrine (PE) were also measured. Additionally, metabolic parameters and expression of some targets associated with vascular and insulin signaling were determined. We demonstrated that the responses to ACh and SNP were severely impaired in the prediabetic state (PD OVX) rats, while E treatment restored vasorelaxation in the PD OVX + E. Moreover, the responses to PE was significantly enhanced in MA of PD OVX groups, regardless of placebo or E treatment. Overall, our data suggest that 1) the impairment of ACh responses in PD OVX rats may, in part, result from the elevated contractile responses to PE, loss of contribution of endothelium-dependent hyperpolarization (EDH) to vasorelaxation, and a decreased sensitivity of MA to nitric oxide (NO), and 2) the basis for the protective effects of E may be partly attributed to the elevation of the NO contribution to vasorelaxation and its interaction with MA as well as potential improvement of insulin signaling. Here, we provide the first evidence of the role of E in protecting MA from early vascular dysfunction in prediabetic female rats.
我们最近报道，早在糖尿病前期状态，加州大学戴维斯分校2型糖尿病（UCD-T2DM）大鼠的肠系膜动脉功能就存在性别差异。我们报道，与糖尿病前期雌性大鼠相比，糖尿病前期雄性大鼠的肠系膜动脉（MA）损伤更严重。然而，当雌性大鼠患糖尿病时，它们表现出比雄性大鼠更严重的血管功能障碍。因此，本研究的目的是调查女性性激素雌激素是否能在糖尿病前期早期状态下保护UCD-T2DM雌性大鼠的肠系膜动脉血管舒张功能。将年龄匹配的雌性斯普拉格-道利大鼠和糖尿病前期（PD）UCD-T2DM大鼠进行卵巢切除（OVX），并皮下植入安慰剂或17β-雌二醇（E 1.5毫克）微丸，持续45天。我们使用药理学抑制剂评估了内皮源性舒张因子（EDRF）对乙酰胆碱（ACh）诱导的血管舒张的贡献。还测量了对硝普钠（SNP）和去氧肾上腺素（PE）的反应。此外，还测定了代谢参数以及与血管和胰岛素信号相关的一些靶点的表达。我们证明，在糖尿病前期状态（PD OVX）大鼠中，对ACh和SNP的反应严重受损，而E治疗可恢复PD OVX + E组的血管舒张功能。此外，无论接受安慰剂还是E治疗，PD OVX组MA对PE的反应均显著增强。总体而言，我们的数据表明：1）PD OVX大鼠中ACh反应受损可能部分是由于对PE的收缩反应增强、内皮依赖性超极化（EDH）对血管舒张的贡献丧失以及MA对一氧化氮（NO）的敏感性降低；2）E的保护作用的基础可能部分归因于NO对血管舒张的贡献增加及其与MA的相互作用以及胰岛素信号的潜在改善。在此，我们首次提供了证据，证明E在保护糖尿病前期雌性大鼠的MA免受早期血管功能障碍方面的作用。
