The indigenous populations living at high mountain
The indigenous populations living at high mountain regions of the Himalayas represent successful human WYE-132 to hypoxia. These populations have undergone selective positive natural selection over millennia across several genomic loci and exhibit unique respiratory, cardiopulmonary and haematological adaptations . The Tibetan pattern of high altitude adaptation is characterized by low haemoglobin concentrations, higher hypoxic ventilatory response and lower incidences of acute mountain sickness (AMS) . Biological anthropology investigations for hypoxia adaptation have identified significant higher order of magnitude of NO and associated metabolites in lung, plasma and red blood cells in Tibetans than low land populations regardless of altitude [6,7]. Similar trends for circulatory NO metabolites has been observed for native Ladakhi residents of southern side of the Himalayas [8,9]. These studies emphasize that higher NO bioavailability ensures higher blood flow and consequently increased oxygen delivery promoting adaptation to hypoxia.
The endothelial isoform of nitric oxide synthase (eNOS) enzymatically produces NO by converting l-arginine to l-citrulline in an oxygen dependent reaction. The enzyme also requires NADPH and cofactors FAD, FMN in its dimeric structure to bind BH4 and l-arginine for effective NO production. Once produced, NO freely diffuses into smooth muscle cells to activate soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP) leading to vasodilatation. The activity of eNOS is modulated by calcium concentration, interactions with other proteins (like caveolin-1, calmodulin and heat shock protein 90) and many cellular events like post-translational modifications (phosphorylation, thiopalmitoylation, S-nitrosylation, acetylation, glycosylation, S-glutathionylation). However, eNOS can exist in two functional states producing NO (dimer) or O2− (monomer or uncoupled) exerting dual effect on vascular function. In the absence of substrate l-arginine as well as oxidation of BH4 and zinc-thiolate centre of eNOS by reactive oxygen and nitrogen species (RONS) dissociates the dimers into monomers making it a superoxide producing enzyme . Recently, nitrate and nitrite, the oxidation products of NO has emerged as reservoir for NO. Under hypoxic and anoxic conditions, xanthine oxidoreductase and mitochondrial cytochrome c oxidase mediate the production of NO from nitrate and nitrite in the vascular wall .
There exists a gender difference in circulatory NO metabolites. Tibetan women possess higher plasma nitrite and lower nitrate than Tibetan men whereas no gender differences exist in plasma nitrite or nitrate content in the lowland subjects . Women undergo myriad physiological changes at high altitude as hypoxia challenges reproductive fitness and neonatal well being. Chronic hypoxia exposure restricts fetal growth, reduces birth weight and increase infant mortality rates [12,13] by elevating maternal circulating vasoconstrictors as compared to vasodilators . Interestingly, high altitude women have developed mechanisms to counter hypoxia associated reductions in birth weight and IUGR as compared to new populations at high altitude . Recent studies have reported that Tibetan women are protected from IUGR and reproductive loss at high altitude as compared to Han Chinese populations [4,12].
Materials and methods
Discussion Monitoring physiological parameters of Ladakhi women, we observed better arterial oxygen saturations (SpO2) as compared to previously reported acclimatized lowlanders [18,19]. Our observed SpO2 values were at par with the high altitude ethnic women of Spiti Valley of Greater Himalayas residing at an altitude of 3000 m–4200 m  and Aymara native women of the Andean plateau residing at 3900–4000 m . Reduced SpO2 at rest is an indicator of inadequate acclimatization to hypoxia and successful climbers maintain higher oxygen saturation levels both at rest and exercise [18,22]. We also observed significant higher resting heart rate (HR) for Ladakhi women and the values were well within the stated range of American Heart Association . There was an evident prehypertensive blood pressure in Ladakhi women as compared to lowlanders [23,24]. The natives of Leh, Ladakh exhibit higher diastolic blood pressure and HR as compared to lowland populations  as a hypoxia adaptive phenotype. During hypoxia exposure, transcription factors HIF-1α and HIF-2α orchestrate time-dependent regulation of cardiorespiratory and haematological responses to ensure O2 transport (O2 transport = arterial oxygen content x blood flow) . In corroboration, we observed higher levels of HIF-1α mRNA and protein in Ladakhi women. These observations support physiological adaptations of Ladakhi women ensuring better oxygen availability under persistent hypobaric hypoxia.