Abstract 8926: Rosiglitazone Acutely Improves Flow Mediated Dilation and Favorably Alters Endothelial Microparticle and Progenitor Cell Numbers in Euglycemic, Senescent Monkeys

Abstract

Background: Rosiglitazone, 6 hours after dosing, rapidly increases endothelial-dependent flow mediated dilation (FMD) in subjects with healthy endothelium. Whether this acute improvement in FMD occurs in the presence of endothelial dysfunction is unknown. We test the hypothesis that rosiglitazone acutely improves FMD in senescent monkeys with endothelial dysfunction and that the improvement coincides with favorable changes in circulating biomarkers of endothelial health, endothelial progenitor cells (EPC) and endothelial microparticles (EMP). Euglycemic monkeys were used to avoid rosiglitazone’s glucose-lowering effects. Methods and Results: In a crossover design, 6 fasted M. fascicularis monkeys (5M/1F; 17 ± 1 yr) were dosed ≥2 weeks apart with vehicle or rosiglitazone at a dose (1 mg/kg, PO) that did not affect baseline hemodynamics, fasting plasma glucose (65 ± 6 mg/dL), insulin (10 ± 3 µlU/mL), total cholesterol (79 ± 7 mg/dL) or triglycerides (59 ± 6 mg/dL). EPC and EMP were sampled 6 h after dosing and measured by flow cytometry. Monkeys were then sedated (midazolam + torbugesic) and baseline femoral artery diameter (4mm segment) measured by ultrasonography. FMD was calculated as the peak %change from baseline following a 5-minute cessation of blood flow below the knee. FMD was lower in these monkeys (17.6 ± 1.3%) vs. young adults (≥25%). Rosiglitazone (vs. vehicle) increased (p<0.01) FMD to 21.3 ± 1.6% (vs.16.9 ± 1.4%) without affecting baseline diameter (1.52 ± 0.04 vs.1.51 ± 0.04 mm). Rosiglitazone (vs. vehicle) increased (p<0.01) EPC [CD45- CD31+ CD34+ VEGFR2+] to 7116 ± 1296 (vs. 4786 ± 1102) cells/ml and decreased (p<0.04) EMP [CD45- CD42a- CD54(ICAM-1)+] to 26669 ± 11112 (vs. 62245 ± 9772) EMP/ml; EMP [CD45- CD42a- CD105(endoglin)+] and EMP [CD45- CD42a- CD144(VE-cadherin)+] also trended lower. (Mean ± SEM; paired t-test). Conclusion: Rosiglitazone acutely improves the endothelial dysfunction in senescent monkeys. This increased FMD is independent of its metabolic effects on glucose and lipids and coincides with stimulation of EPC and with suppression of EMP linked to endothelial cell adhesion and potentially apoptosis. Whether these EPC and EMP changes directly contribute to the enhanced endothelial function warrants further study.