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.