Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations ofVEGFAin Sherpa highlanders

Abstract

24Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, 25 partly by one of the adaptation mechanisms promoting increases of microcirculatory 26 blood flow and capillary density at high altitude for restoring oxygen supply to tissues. 27 Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important 28 signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our 29 present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 30 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, 31 we measured plasma VEGF-A concentrations and genotyped five single-nucleotide 32 polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in 33 the 5ʹ-untranslated region (5ʹ-UTR); and rs3025039 in the 3ʹ-UTR. The average 34 circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 35 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele 36 discriminations for the analyzed SNPs revealed significant genetic divergences of 37 rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa 38 lowlanders, East Asians, South Asians, and the global population; however, consistency 39 with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the 40 SNP rs3025039 in the 3ʹ-UTR presented constant preserved genetic variation among 41 global populations. Our findings indicated that the physiological sea-level VEGF-A 42 concentration in Sherpa highlanders at high altitude was probably linked with the 43 significant variations of VEGFA in Sherpas that regulate the gene expression in a manner 44 of tolerance to hypoxia through production of the optimal biological level of VEGF-A at 45 high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of 46 capillary density and microcirculation, providing efficient and effective diffusion of 3 47 oxygen to tissues and representing human adaptation to high-altitude hypoxia 48 environment. 49 Author summary 50 Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, 51 partly by one of the adaptation mechanisms promoting increases of microcirculatory 52 blood flow and capillary density at high altitude for restoring oxygen supply to tissues. 53 Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an 54 important signaling protein involved in hypoxia-stimulated vasculogenesis and 55 angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa 56 highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination 57 of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant 58 divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region 59 in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, 60 and the global population; however, consistency w...

Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season

“…However, human studies reported conflicting data regarding circulating VEGF-A levels in healthy sea level residents during short-term exposure to high altitudes [61,62]. Chronic exposure to hypoxia seems not to be associated with increased systemic VEGF levels in well-adapted Sherpa highlanders {Droma, 2020 #12125} [63]. Interestingly, patients with chronic mountain sickness exhibited higher VEGF expression compared to healthy Andean highlanders despite comparable peripheral oxygen saturation levels [64].…”