Date of Award


Document Type


Degree Name

Doctor of Philosophy (Ph.D.)


Pharmaceutical and Chemical Sciences

First Advisor

Roshanak Rahimian

First Committee Member

James Uchizono

Second Committee Member

John Livesey

Third Committee Member

David Thomas

Fourth Committee Member

Aditya Goel


The studies in this dissertation were designed to investigate the impacts of estrogen (17-β estradiol/E2) and moderate-intensity exercise (MIE) on the mesenteric arterial (MA) function of the University of California Davis type-2 diabetes mellitus (UCD-T2DM) Rat model. Our recent report suggests that diabetes impairs MA vasorelaxation in both sexes of the UCD-T2DM model. Particularly, we reported that MA from prediabetic male rats showed a greater impairment compared to that in prediabetic females. However, when females become diabetic, they exhibit a greater vascular dysfunction than males. Therefore, the aim of the first study was to investigate whether female sex hormone, specifically E2, preserves the MA vasorelaxation in female UCD-T2DM rats at the early prediabetic state. For this study, age-matched healthy Sprague Dawley (SD) and prediabetic female UCD-T2DM rats were ovariectomized and subcutaneously implanted with either a placebo or E2 pellet for 45 days. Regular aerobic exercise is a well-known therapeutic intervention for endothelial dysfunction, insulin resistance, and cardiovascular disease (CVD) risk in diabetes. However, there are still debates about the duration, intensity, and underlying mechanisms of benefits of exercise against deleterious metabolic consequences in diabetic patients. In the second study outlined in this dissertation, we examined the impact of exercise training on vascular function and wall structure of the UCD-T2DM male rats. Age-matched male diabetic and SD control rats were randomly divided into sedentary and exercise-trained groups. The exercise-trained groups ran on a treadmill for eight weeks (1hr/day, 5days per week). For both studies (Studies I & II), metabolic parameters and MA responses to vasodilator and vasocontractile agents were determined. Furthermore, the expression of molecules associated with vascular signaling were also analyzed.

The specific aims of our studies were to investigate whether E2 and moderate-intensity exercise (MIE) alter the 1) endothelium-dependent vasorelaxation (EDV) and vasoconstriction 2) relative contribution of endothelium-derived relaxing factors (EDRF) to vasorelaxation, and 3) expression of proteins associated with vascular signaling, in MA of UCD-T2DM rats.

In the first study, we demonstrated that acetylcholine (ACh)-induced vasorelaxation was impaired in MA of ovariectomized (OVX) prediabetic UCD-T2DM rats. Our data also showed that E2 replacement improved MA relaxation in OVX prediabetic group to a similar level to that in control groups. Inhibition of cyclooxygenase (COX) by indomethacin (Indo) did not significantly affect the vascular responses in any groups, suggesting a minor role of COX metabolites in MA relaxation in the experimental groups. Inhibition of nitric oxide (NO) synthase (NOS) by L-NAME reduced vasorelaxation to ACh in control groups, but it did not completely abolish the vasorelaxation. We also showed that in control (healthy) groups, both NO and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation were dominant in the MA relaxation of placebo and E2 treated rats. However, in prediabetic groups, L-NAME completely abolished the vasorelaxation, regardless of E2 treatment, suggesting a relative shift from EDHF-type relaxation to only NO-mediated relaxation in these groups. Furthermore, the sensitivity of MA to NO was significantly impaired in OVX prediabetic group, but E2 treatment enhanced the MA sensitivity to NO. Overall, our data suggest that a greater vasorelaxation in the E2 treated OVX prediabetic group could be partly attributed to the elevated role of NO or improved sensitivity of MA to NO in this group.

The second study demonstrated that ACh-induced vasorelaxation of MA was significantly impaired in sedentary diabetic (DS) male rats. MIE significantly enhanced MA vasorelaxation in the exercise-trained diabetic (DE) group compared to the DS. However, no significant differences were observed between the vasorelaxation of control sedentary (CS) and control exercise-trained groups (CE). Inhibition of COX enhanced maximal vasorelaxation response (Rmax) to ACh in DS arteries suggesting an elevated contractile COX contribution in MA of this group which could possibly be due to the observed increase in COX expression in the DS group. Unlike the DS group, inhibition of COX did not affect the vasorelaxation responses to ACh in the DE group. The addition of L-NAME resulted in a reduction in ACh-induced relaxation of MA from both DS and DE groups. However, the effect of L-NAME was more prominent in the DS group compared to the DE group, suggesting a major contribution of NO in DS arteries. On the other hand, a preserved role of NO with an enhanced EDHF-mediated relaxation was observed in the MA vasorelaxation of the DE group. Our data on the elevated small conductance calcium-activated potassium channel (SKCa) expression level in MA taken from the DE group compared to that in the DS group may suggest a role for SKCa in increased EDHF-type relaxation in the DE group. Furthermore, DS arteries exhibited a higher contractile response, myogenic tone, and wall thickness than those in MA of DE. Overall, our data suggest that MIE reduced myogenic tone (DE vs. DS) and improved EDV in mesenteric arteries of diabetic rats, possibly via a shift from contractile COX activity to both NO and EDHF-type relaxation.

In conclusion, the data generated in study-I suggest that estrogen may protect prediabetic female MA from early vascular dysfunction, possibly by elevating the contribution of NO to vasorelaxation as a compensatory mechanism to the loss of EDHF-type relaxation in this group. Although the results of the current study are in agreement with our previous report demonstrating a possible protective effect of female sex hormones in the MA function at prediabetic state, additional studies are needed to establish the specific role of E2 in the progression of vascular dysfunction in the diabetic state.

Lastly, an intriguing observation of study-II was that MIE improved vasorelaxation and prevented the loss of EDHF-type relaxation in diabetic arteries. This was in addition to the changes induced to the wall thickness and myogenic tone in arteries of UCD-T2DM males. Given that sex differences play an important role in cardiovascular physiology, additional studies are needed to establish the specific role of MIE on vascular dysfunction in UCD-T2DM female rats and its underlying mechanisms.





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