Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II–Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm

摘要

GTPCH (GTP cyclohydrolase 1, encoded by Gch1) is required for the synthesis of tetrahydrobiopterin; a criticalregulator of endothelial NO synthase function. We have previously shown that mice with selective loss of Gch1 inendothelial cells have mild vascular dysfunction, but the consequences of endothelial cell tetrahydrobiopterin deficiencyin vascular disease pathogenesis are unknown. We investigated the pathological consequence of Ang (angiotensin) IIinfusion in endothelial cell Gch1 deficient (Gch1 fl/fl Tie2cre) mice. Ang II (0.4 mg/kg per day, delivered by osmoticminipump) caused a significant decrease in circulating tetrahydrobiopterin levels in Gch1 fl/fl Tie2cre mice and a significantincrease in the Nω-nitro-L-arginine methyl ester inhabitable production of H 2 O 2 in the aorta. Chronic treatment with thissubpressor dose of Ang II resulted in a significant increase in blood pressure only in Gch1 fl/fl Tie2cre mice. This findingwas mirrored with acute administration of Ang II, where increased sensitivity to Ang II was observed at both pressorand subpressor doses. Chronic Ang II infusion in Gch1 fl/fl Tie2ce mice resulted in vascular dysfunction in resistancemesenteric arteries with an enhanced constrictor and decreased dilator response and medial hypertrophy. Alteredvascular remodeling was also observed in the aorta with an increase in the incidence of abdominal aortic aneurysmformation in Gch1 fl/fl Tie2ce mice. These findings indicate a specific requirement for endothelial cell tetrahydrobiopterinin modulating the hemodynamic and structural changes induced by Ang II, through modulation of blood pressure,structural changes in resistance vessels, and aneurysm formation in the aorta.