title: Pulmonary hypertension in the newborn GTP cyclohydrolase I-deficient mouse.
abstract: Tetrahydrobiopterin (BH4) is a regulator of endothelial nitric oxide synthase (eNOS) activity. Deficient levels result in eNOS uncoupling, with a shift from nitric oxide to superoxide generation. The hph-1 mutant mouse has deficient GTP cyclohydrolase I (GTPCH1) activity, resulting in low BH4 tissue content. The adult hph-1 mouse has pulmonary hypertension, but whether such condition is present from birth is not known. Thus, we evaluated newborn animals' pulmonary arterial medial thickness, biopterin content (BH4+BH2), H(2)O(2) and eNOS, right ventricle-to-left ventricle+septum (RV/LV+septum) ratio, near-resistance pulmonary artery agonist-induced force, and endothelium-dependent and -independent relaxation. The lung biopterin content was inversely related to age for both types, but significantly lower in hph-1 mice, compared to wild-type animals. As judged by the RV/LV+septum ratio, newborn hph-1 mice have pulmonary hypertension and, after a 2-week 13% oxygen exposure, the ratios were similar in both types. The pulmonary arterial agonist-induced force was reduced (P<0.01) in hph-1 animals and no type-dependent difference in endothelium-dependent or -independent vasorelaxation was observed. Compared to wild-type mice, the lung H(2)O(2) content was increased, whereas the eNOS expression was decreased (P<0.01) in hph-1 animals. The pulmonary arterial medial thickness, a surrogate marker of vascular remodeling, was increased (P<0.01) in hph-1 compared to wild-type mice. In conclusion, our data suggest that pulmonary hypertension is present from birth in the GTPCH1-deficient mice, not as a result of impaired vasodilation, but secondary to vascular remodeling.
authors: Department of Paediatrics, The Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON M5G 1X8, Canada. Jaques.Belik@SickKids.ca
authors: Jaques
authors: J
authors: Belik
authors: Brendan A S
authors: BA
authors: McIntyre
authors: Masahiro
authors: M
authors: Enomoto
authors: Jingyi
authors: J
authors: Pan
authors: Hartmut
authors: H
authors: Grasemann
authors: Jeannette
authors: J
authors: Vasquez-Vivar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D006136:GTP Cyclohydrolase / Q000172:deficiency / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA
chemical_list: D006136:GTP Cyclohydrolase