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OS 21-06 THREE-MONTH EXPOSURE TO ENDOTHELIN-1 OVEREXPRESSION INCREASES BLOOD PRESSURE AND CAUSES SMALL ARTERY INJURY

Objective: The mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells are complex and remain unclear. Recently, we developed a transgenic mouse with tamoxifen-inducible endothelium-restricted human ET-1 overexpression (ieET-1) using Cre/loxP technology. ieET-1 mice exhibited a BP increase after three weeks of induction in an ET type A receptor-dependent manner, in absence of evident vascular injury. It is unknown whether long-term exposure to ET-1 overexpression results in persistent BP elevation and vascular injury. Design and Method: Nine to 12-week old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase under the control of endothelium-specific Tie2 promoter, were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and studied 3 months later. BP by telemetry, mesenteric artery (MA) endothelial function and vascular remodeling using pressurized myography and reactive oxygen species (ROS) generation using dihydroethidium staining and immune cell infiltration by immunofluorescence in MA or perivascular fat (PVAT) were determined at the end of the study. Results: Systolic BP was increased by 27 mmHg in ieET-1 compared with ieCre mice (P < 0.001). Endothelium-dependent relaxation responses to acetylcholine were decreased by 50% in ieET-1 compared to ieCre mice (P < 0.01), whereas endothelium-independent relaxation to sodium nitroprusside were unchanged. MA media/lumen and media cross-sectional area were similar in both groups, but stiffness was increased in ieET-1 compared to ieCre mice, as indicated by leftward displacement of the stress-strain curves (14% decrease in strain at 140 mmHg, P < 0.05). ROS generation was enhanced 1.5-fold in PVAT of ieET-1 compared to ieCre mice (P < 0.05). Monocyte/macrophage infiltration was similar whereas CD3+ cell infiltration was 1.4-fold higher in MA PVAT of ieET-1. Conclusions: The results demonstrate that long-term exposure to endothelial ET-1 overexpression caused sustained BP elevation, endothelial dysfunction and vascular stiffening, oxidative stress and CD3+ cell infiltration.