Rosiglitazone reverses endothelial dysfunction but not remodeling of femoral artery in Zucker diabetic fatty rats

Abstract

Objectives: Endothelial dysfunction precedes atherogenesis and clinical complications in type 2 diabetes. The vascular dysfunction in Zucker diabetic fatty (ZDF) rats was evaluated at different ages along with the effect of treatment with rosiglitazone (Rosi) on endothelial function and mechanical remodeling.

Methods: The Rosi treatment was given to ZDF rats for 3 weeks. The endothelium-dependent vasodilation and alpha-adrenoceptor-dependent vasoconstriction of femoral arteries were studied using an ex-vivo isovolumic myograph. The biomechanical passive property of the arteries was studied in Ca2+-free condition. The expressions of endothelial nitric oxide synthase (eNOS), alpha-adrenoceptor, matrix metalloproteinase 9 (MMP9), and elastase were evaluated.

Results: Endothelium-dependent vasorelaxation of the femoral artery was blunted at low doses in ZDF rats at 11 weeks of age and attenuated at all doses in ZDF rats at 19 weeks of age. The expression of eNOS was consistent with the endothelium-dependent vasorelaxation. The alpha-adrenoceptor was activated and the mechanical elastic modulus was increased in ZDF rats at 19 weeks of age. The expressions of alpha-adrenoceptor, MMP9, and elastase were up regulated in ZDF rats at 19 weeks of age. Rosi treatment for 3 weeks restored endothelium-dependent vasorelaxation and the expression of eNOS and the adrenoceptor activation at the doses below 10-6 mole/L in ZDF rats at 19 weeks of age. Rosi treatment for 3 weeks did not, however, improve the mechanical properties of blood vessel, the expressions of alpha-adrenoceptor, MMP9, and elastase in ZDF rats.

Conclusion: The endothelial dysfunction and mechanical remodeling are observed as early as 19 weeks of age in ZDF rat. Rosi treatment for 3 weeks improves endothelial function but not mechanical properties.

Figure 1

The endothelium-dependent dose-response vasorelaxation for the various groups. A: Effect of age (11 wks and 19 wks) on the vasorelaxation of ZDF rats in comparison with lean rats. B: Effects of Rosi on the vasorelaxation of ZDF rats in comparison with lean rats. Lean: Zucker lean rats. ZDF: ZDF rats. Rosi: rosiglitazone treatment. 11w: 11 weeks of age. 19w: 19 weeks of age. #: ANOVA analysis indicates statistical difference (p < 0.05) of the dose-dependent curve between the ZDF rats at different age and lean rats. *: Significant difference (p < 0.05) at single dose between ZDF rats at different age and lean rats.

Figure 2

The deleteriousness effect of acute over-inflation on the endothelium-dependent (ACh) and endothelium-independent (SNP) vasorelaxation. Lean: Zucker lean rats. ZDF: ZDF rats. Rosi: rosiglitazone treatment. 19w: 19 weeks of age. #: ANOVA analysis indicates statistical difference (p < 0.05) of the dose-response curves of ZDF rats between SNP and ACh during acute over-inflation. *: Significant difference (p < 0.05) at the single dose between lean and ZDF rats during acute over-distension.

Figure 3

The dose-response relation of circumferential tension for the various groups. A: Effect of age (11 weeks and 19 weeks) on vasoconstriction. B: Effects of Rosi treatment on vasoconstriction. Lean: Zucker lean rats. ZDF: ZDF rats. Rosi: rosiglitazone treatment. 11w: 11 weeks of age. 19w: 19 weeks of age. #: ANOVA indicates significant difference (p < 0.05) of the dose-response curve between the ZDF rats at different age and lean rats. *: Statistical difference (p < 0.05) at single dose between ZDF rats at different age and lean rats.

Figure 4

The passive pressure-diameter relationship of the femoral artery. The vessel segment was fully relaxed in Ca²⁺ free PSS at 37°C. A: The animals in different ages: lean rats (11 weeks of age and 19 weeks of age) and ZDF rats (11 weeks of age). There is no significant difference of pressure-diameter relationship among the three groups. B: The animals in different groups: age-matched lean rats (19 weeks of age), ZDF rats (19 weeks of ages), and ZDF rats treated with Rosi. There is significant shift of diameter in ZDF rats at 19 weeks of age and Rosi treated ZDF rats in comparison with age-matched lean rats. Lean: Zucker lean rats. ZDF: ZDF rats. Rosi: rosiglitazone treatment. 11w: 11 weeks of age. 19w: 19 weeks of age. * p < 0.05 indicates the statistical significance between groups using ANONA analysis.

Figure 5

The Kirchhoff stress- Green strain relationship of the femoral artery. A: The animals in different ages: lean rats (11 weeks of age and 19 weeks of age) and ZDF rats (11 weeks of age). There is no significant difference of stress-strain relationship among the three groups. B: The animals in different groups: age-matched lean rats (19 weeks of age), ZDF rats (19 weeks of age), and ZDF rats treated with Rosi. In 19 weeks of age, the stress-strain curve of ZDF rats was significantly shifted to left. The Rosi treatment did not reverse the mechanical properties of the arteries. * p < 0.05 indicates the statistical significance between groups using ANONA analysis. C: The elastic moduli at the pressure near physiological state. Lean: Zucker lean rats. ZDF: ZDF rats. Rosi: rosiglitazone treatment. 11w: 11 weeks of age. 19w: 19 weeks of age. * p < 0.05 indicates the statistical significance in comparison with lean rats using student t-test.

Figure 6

The vascular expressions of eNOS, α-adrenoceptor (α-AR), MMP9, and elastase. In all four sections, top panel is the bands of proteins and bottom panel is the percent intensity of the ratio of the bands to β-actin. A: The expression of eNOS. B: The expressions of α-adrenoceptor. C: The expressions of MMP9. D: The expression of elastase. Lean: Zucker lean rats. ZDF: ZDF rats. 11w: 11 weeks of age. 19w: 19 weeks of age. 19w + V: 19 weeks of age treated with vehicle. 19w + R: 19 weeks of age treated with Rosi. * p < 0.05 indicates statistical significance when compared with lean rats using student t-test. # p < 0.05 indicates statistical significance in comparison of the two groups using student t-test.