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2018 ; 72
(1
): 128-138
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Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin)
II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm
#MMPMID29844152
Chuaiphichai S
; Rashbrook VS
; Hale AB
; Trelfa L
; Patel J
; McNeill E
; Lygate CA
; Channon KM
; Douglas G
Hypertension
2018[Jul]; 72
(1
): 128-138
PMID29844152
show ga
GTPCH (GTP cyclohydrolase 1, encoded by Gch1) is required for the synthesis of
tetrahydrobiopterin; a critical regulator of endothelial NO synthase 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
tetrahydrobiopterin deficiency in vascular disease pathogenesis are unknown. We
investigated the pathological consequence of Ang (angiotensin) II infusion in
endothelial cell Gch1 deficient (Gch1(fl/fl) Tie2cre) mice. Ang II (0.4 mg/kg per
day, delivered by osmotic minipump) caused a significant decrease in circulating
tetrahydrobiopterin levels in Gch1(fl/fl) Tie2cre mice and a significant increase
in the N?-nitro-L-arginine methyl ester inhabitable production of H(2)O(2) in the
aorta. Chronic treatment with this subpressor dose of Ang II resulted in a
significant increase in blood pressure only in Gch1(fl/fl) Tie2cre 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 Gch1(fl/fl) Tie2ce mice resulted in vascular dysfunction in
resistance mesenteric arteries with an enhanced constrictor and decreased dilator
response and medial hypertrophy. Altered vascular remodeling was also observed in
the aorta with an increase in the incidence of abdominal aortic aneurysm
formation in Gch1(fl/fl) Tie2ce mice. These findings indicate a specific
requirement for endothelial cell tetrahydrobiopterin 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.