GCH1 contributes to high-altitude adaptation in Tibetans by regulating blood nitric oxide

Nitric oxide (NO) is a key vasodilator that regulates vascular pressure and blood flow. Tibetans have developed a "blunted" mechanism for regulating NO levels at high altitude, with GTP cyclohydrolase 1 (GCH1) identified as a key candidate gene. Here, we present comprehensive genetic and functional analyses of GCH1, which exhibits strong Darwinian positive selection in Tibetans. We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans. Based on this observation, we generate the heterozygous Gch1 knockout (Gch1^+/-) mouse model to simulate its downregulation in Tibetans. We find that under prolonged hypoxia, the Gch1^+/- mice have relatively higher blood NO and blood oxygen saturation levels compared with the wild-type (WT) controls, providing better oxygen supplies to the cardiovascular and pulmonary systems. Markedly, hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1^+/- mice compared with the WT controls, likely due to the adaptive changes in molecular regulations related to metabolism, inflammation, circadian rhythm, extracellular matrix, and oxidative stress. This study sheds light on the role of GCH1 in regulating blood NO, contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.