Estrogen receptor (ESR1 and ESR2)-mediated activation of eNOS–NO–cGMP pathway facilitates high altitude acclimatization

Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress

“…The production of NO increased and oxidative stress was reduced [84,[192][193][194][195] ERα activated eNOS through the PI3/AKT signal pathway The production of NO increased and oxidative stress was reduced [175,189,195] Estrogen increased the intracellular availability of the eNOS cofactor BH4 and prevented the uncoupling of eNOS The production of eNOS-dependent ROS was reduced [177,178] 7 Oxidative Medicine and Cellular Longevity muscle cells [171]. Wassmann et al [172] demonstrated that raloxifene, a selective estrogen receptor modulator, increases the bioavailability of NO by upregulating eNOS mRNA and activity in the aorta of spontaneously hypertensive rats.…”

Association Between 17β-Estradiol Receptors and Nitric Oxide Signaling Augments High-Altitude Adaptation of Ladakhi Highlanders

“…These cumulative results further support enhanced E2 availability and E2-ESR1-/ESR2-mediated signaling conferring vascular adaptive features to Ladakhi highlanders. Epidemiological data, experimental and clinical evidence, have demonstrated that E2 regulates cardiovascular physiological function and features by increasing NO availability (Mendelsohn and Karas, 1999;Vitale et al, 2009;Pooja et al, 2020). E2 also plays a crucial role in the ability of resistance arteries to remodel in response to long- term increase in blood flow, which is necessary to optimize tissue perfusion (Tarhouni et al, 2014).…”

“…It is important to note that estrogen prevents excessive erythropoiesis and CMS in females at high altitude (Azad et al, 2020). Recent wholegenome sequencing combined with selection statistics studies has identified positive natural selection of E2 receptors (ESR1) and plasma membrane E2 receptor signaling pathway for Himalayan highlanders (Gnecchi-Ruscone et al, 2018), and positively associated with higher NO availability at Himalayas (Pooja et al, 2020). These observations emphasize population-specific regulation of steroidogenic hormones, especially T and E2, which confer adaptive features to native highlanders, although their precise role remains to be elucidated.…”

Mean Pulmonary Arterial Pressure Decreases with Exposure Time in the Tibet Plateau

“…This SNP marks the location of splicing variant of alternative splicing of EPAS1 mRNA, which is expressed by humans at high altitudes. Humans living at high-altitude by activating a series of compensatory reactions occur in the respiratory system, sympathetic nervous system, cardiovascular system, central nervous system and blood system to alleviate the symptoms of hypoxia, a process known as highaltitude acclimatization [21,22]. The current scientific studies have shown that circulating metabolites of NO and NO derived in the lungs are significant factors for high-altitude adaptation [23].…”

“…Endogenous NO produced by endothelial nitric oxide synthase plays an important role in the relaxation of vascular tension [26]. In endothelial cells, nitric oxide (NO) as a major signaling molecules regulating pulmonary vasodilation, it is produced by endothelial nitric oxide synthase (eNOS) and triggers the soluble guanosine cyclase in vascular smooth muscle to produce cGMP, thus promote vasodilation [21,[27][28][29][30] eNOS is mainly distributed in endothelial cells and circulating blood cells. In the cardiovascular system, eNOS is a regulator of blood flow, leukocyte adhesion and migration, and an inhibitor of platelet activation and aggregation [30].…”