Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Roshanak Rahimian

First Committee Member

Aditya Goel

Second Committee Member

Timothy Smith

Third Committee Member

David Thomas

Fourth Committee Member

James A. Uchizono

Abstract

Little is known about the interaction between diabetes and sex in vasculature. This study was designed to investigate the effects of estrogen as well as type 2 diabetes (T2D) on aortic function in rats with respect to sex. To test the effects of T2D and sex, UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model was used. To study the effects of estrogen, ovariectomized Sprague- Dawley female rats and UCD-T2DM rats at pre-diabetic stage were used and the rats were implanted subcutaneously either with placebo or 17 β-estradiol pellets (60 days release, 1.5mg/pellets). The plasma analytes for metabolic parameters and aortic responses to vasodilator and vasoconstrictor agents were determined. The expression of molecules associated with vascular response (e.g. endothelial nitric oxide (NO) synthase (eNOS), Nox1, Nox4, intermediate conductance calcium-dependent potassium channels (IKCa) and small conductance calcium-dependent potassium channels (SKCa)) were also evaluated in aortic tissue.

The main objectives of the study were whether 1) sex differences exist in the development of abnormal vascular responses of UCD-T2DM rats, 2) there were changes in the relative contributions of endothelium-derived relaxing factors (EDRFs) in modulating vascular reactivity of aorta, and 3) estrogen replacement improves the aortic function of ovariectomized UCD-T2DM rats at pre-diabetic stage.

In the study of examining the effect of sex and T2D, diabetes significantly impaired relaxation responses to ACh and SNP in aortic rings from female UCD-T2DM rats, however, potentiated the relaxation in males. The responsiveness to PE was significantly enhanced in both diabetic groups regardless of sex. Accordingly, the basal nitric oxide (NO), as indicated by the potentiation of the response to PE after L-NAME, was reduced in aorta of both diabetic groups. Blocking of COX, sGC and NOS completely abolished the relaxation response in female diabetic group whereas male diabetic animals showed a significant remaining relaxation response to ACh. Further incubation of aortic rings of male animals with TEA or TRAM 34 blunted the relaxation responses to ACh in both control and diabetic groups. However, the inhibitory effects of TEA or TRAM 34 on the ACh-induced relaxation in male UCD-T2DM group was greater than their respective controls. By contrast, ACh responses were not affected following incubation with Apamin in either group of male rats. Moreover, protein expression of IKca were significantly higher in male diabetic group compared with the respective controls.

In the estrogen replacement study, treatment with E2 markedly enhanced the ACh responses of aortic rings in both control and pre-diabetic groups compared to respective placebo treated group. Moreover, effect of E2 in improving the ACh induced relaxation response was significantly higher in control group compared with pre-diabetic animals. The responsiveness to PE were significantly reduced in both E2 treated groups. Basal NO level was significantly higher in both E2 replaced groups but in control group the level was significantly higher than the pre-diabetic rats. Also, protein expression level of Nox1 were decreased in E2 treated control and pre-diabetic group but eNOS were enhanced only in E2 treated control groups.

In conclusion, this study suggests that the effects of type 2 diabetes on aortic ring are sex specific and we showed a differential contribution of EDRFs in male UCD-T2DM rats. Furthermore, our data suggests that elevated eNOS and decreased Nox1protein level may contribute to the higher impact of estrogen in ovariectomized control groups compared to the pre-diabetic rats.

Pages

127

Download

Share

COinS
 

Rights Statement

Rights Statement

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).