Date of Award

5-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering and Sciences

First Advisor

Kenia Pedrosa Nunes

Second Advisor

Ralph Turingan

Third Advisor

Melissa Borgen

Fourth Advisor

Andrew G. Palmer

Abstract

Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat shock protein 70 (HSP70), a family of chaperone proteins, has recently been reported as a key player in vascular reactivity, affecting large blood vessels such as the aorta. Hyperglycemia, a hallmark of diabetes, correlates with the severity of vascular damage and circulating HSP70 levels. In dia- betes, blood vessels often show impaired contractility, contributing to vascular dysfunc- tion. However, the specific role of HSP70 in T2D-related vascular contraction remains unclear. We hypothesized that blocking HSP70 would improve vascular function in a widely used diabetic mouse model (db/db). To test this, we measured both intracellu- lar HSP70 and circulating serum HSP70 levels in control and diabetic male mice using immunofluorescence and Western blotting. We also examined the aorta’s contractile response using a wire myograph system, which measured the force produced in response to phenylephrine (PE), both with and without a pharmacological inhibitor for HSP70,

in aorta from males and females, and after removing extracellular calcium. Our findings show that intracellular HSP70 (iHSP70) levels were similar in the control and diabetic groups, whereas circulating HSP70 (eHSP70) levels were higher in diabetic mice, alter- ing the iHSP70/eHSP70 ratio. Even though VER155008 attenuated both phases of the contractile curve in the diabetic and control groups, enhanced vasoconstriction to PE was observed only in the tonic phase of the curve in the db/db group, and this effect was prevented by iHSP70 inhibition, which involves calcium mobilization, as internal calcium levels in aortic rings treated with VER155008 decreased. In a second batch of experiments, aimed at targeting eHSP70, we exposed diabetic animals to chronic Berberine treatment, the main compound of a well known herb for its hypoglycemic and anti-inflammatory effects and recently reported to target HSP70. Then, we re- evaluate HSP70 levels and aortic vascular function and assess whether the treatment decreases aortic stiffness in diabetes. Results showed that Berberine abolished hyper- contractility in the aortas of diabetic animals, and its effects are HSP70-dependent. Also, the treatment decreases eHSP70 and aortic stiffening in diabetic animals. In conclusion, this study demonstrates that blocking HSP70 improves vascular reactivity in the hyperglycemic state of T2D by restoring proper vascular contraction.

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