GTP cyclohydrolase 1 (GTPCH, encoded by Gch1) is required for the synthesis of tetrahydrobiopterin (BH4); a critical regulator of endothelial NOS (eNOS) function. We have previously shown that mice with selective loss of Gch1 in endothelial cells have mild vascular dysfunction, but the consequences of endothelial cell BH4 deficiency in vascular disease pathogenesis is unknown. We investigated the pathological consequence of angiotensin II (Ang II) infusion in endothelial cell Gch1 deficient (Gch1fl/flTie2cre) mice. Ang II (0.4 mg/kg/day, delivered by osmotic mini pump) caused a significant decrease in circulating BH4 levels in Gch1fl/flTie2cre mice and a significant increase in the L-NAME inhabitable production of H2O2 in the aorta. Chronic treatment with this subpressor dose of Ang II resulted in a significant increase in blood pressure only in Gch1fl/flTie2cre mice. This finding was mirrored with acute administration of Ang II where increased sensitivity to Ang II was observed at both pressor and subpressor doses. Chronic Ang II infusion in Gch1fl/flTie2ce mice resulted in vascular dysfunction in resistance mesenteric arteries with an enhanced constrictor and decreased dilator response, and medial hypertrophy. Altered vascular remodelling was also observed in the aorta with an increase in the incidence of abdominal aortic aneurysm (AAA) formation in Gch1fl/flTie2ce mice. These findings indicate a specific requirement for endothelial cell BH4 in 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.
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