Abstract P062: Long-term Exposure to Endothelin-1 Overexpression Increases Blood Pressure and Causes Small Artery Injury

Abstract

Background: 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 BP rise after three weeks of induction in an ET type A receptor-dependent manner, in absence of vascular and kidney injury. It is unknown whether long-term exposure to ET-1 overexpression results in elevated BP elevation and vascular injury. Methods: Nine to 12-week old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase (CreERT2) under the control of EC-specific Tie2 promoter, were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and studied 3 months later. Metabolic cages were used to collect 24-hour urine for sodium, potassium and protein measurements. Renal artery flow (RAF) was assessed by ultrasonography. BP was determined by telemetry, plasma aldosterone by ELISA, and small mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography. Results: Systolic BP was increased in ieET-1 compared with ieCre mice (144±5 vs 117±3 mmHg, P<0.001). RAF was decreased in ieET-1 compared with control (1.9±0.2 vs 3.0±0.3 mL/min, P<0.01). The excretion of urinary sodium, potassium and protein was similar in both groups. Plasma aldosterone levels were increased in ieET-1 compared with ieCre mice (1.99±0.20 vs 1.29±0.12 ng/mL, P<0.05). Endothelium-dependent relaxation responses to acetylcholine were impaired in ieET-1 compared to ieCre mice (36.3±4.7 vs 71.4±9.7%, P<0.01), whereas endothelium-independent relaxation responses 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 (strain at 140mmHg: 0.61±0.04 vs 0.71±0.02, P<0.05). Conclusions: The results demonstrate that long-term exposure to endothelial ET-1 overexpression caused sustained BP rise and small artery stiffening.