title: Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice.
abstract: Tetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension. The present study thus investigates biopterin metabolism and eNOS expression, as well as the effect of sepiapterin (a precursor of BH4) and eNOS gene deletion, in a mice model of hypoxic pulmonary hypertension. In lungs, chronic hypoxia increased BH4 levels and eNOS expression, without modifying dihydrobiopterin (BH2, the oxidation product of BH4) levels, GTP cyclohydrolase-1 or dihydrofolate reductase expression (two key enzymes regulating BH4 availability). In intrapulmonary arteries, chronic hypoxia also increased expression of eNOS, but did not induce destabilisation of eNOS dimers into monomers. In hypoxic mice, sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy, whereas it modified neither remodelling nor alteration in vasomotor responses (hyper-responsiveness to phenylephrine, decrease in endothelium-dependent relaxation to acetylcholine) in intrapulmonary arteries. Finally, deletion of eNOS gene partially prevented hypoxia-induced increase in right ventricular systolic pressure, right ventricular hypertrophy and remodelling of intrapulmonary arteries. Collectively, these data demonstrate the absence of BH4/BH2 changes and eNOS dimer destabilisation, which may induce eNOS uncoupling during hypoxia-induced pulmonary hypertension. Thus, even though eNOS gene deletion and sepiapterin treatment exert protective effects on hypoxia-induced pulmonary vascular remodelling, increase on right ventricular pressure and / or right ventricular hypertrophy, these effects appear unrelated to biopterin-dependent eNOS uncoupling within pulmonary vasculature of hypoxic wild-type mice.
authors: University Bordeaux, Centre de recherche Cardio-Thoracique de Bordeaux, U1045, Bordeaux, France ; INSERM, Centre de recherche Cardio-Thoracique de Bordeaux, U1045, Bordeaux, France.
authors: Mathilde
authors: M
authors: Dubois
authors: Estelle
authors: E
authors: Delannoy
authors: Lucie
authors: L
authors: Duluc
authors: Ellen
authors: E
authors: Closs
authors: Huige
authors: H
authors: Li
authors: Christian
authors: C
authors: Toussaint
authors: Alain-Pierre
authors: AP
authors: Gadeau
authors: Axel
authors: A
authors: Gödecke
authors: Véronique
authors: V
authors: Freund-Michel
authors: Arnaud
authors: A
authors: Courtois
authors: Roger
authors: R
authors: Marthan
authors: Jean-Pierre
authors: JP
authors: Savineau
authors: Bernard
authors: B
authors: Muller
mesh_terms: D000818:Animals; D001708:Biopterins / Q000378:metabolism*; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications*; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; D013762:Tetrahydrofolate Dehydrogenase