Systemic vascular reactivity during high-altitude pregnancy

There is an increased incidence of preeclampsia at high compared with low altitude. Increased vasoreactivity, possibly due to a deficiency of vasodilator prostaglandins, is thought to contribute to the etiology of preeclampsia. We sought to determine whether high-altitude exposure increased systemic vascular reactivity during pregnancy. We measured systemic vascular reactivity and contractile sensitivity of isolated aortic rings from pregnant and nonpregnant guinea pigs kept for 6 wk at either simulated high altitude (3,900 m) or low altitude (1,600 m). We found that pregnancy at high compared with low altitude increased baseline systemic vascular resistance (SVR) but not the SVR response to angiotensin II in awake unstressed guinea pigs. Contractile sensitivity to norepinephrine was also increased in aortic rings isolated from high-altitude compared with low-altitude pregnant animals. Meclofenamate, a prostaglandin synthesis inhibitor, did not equalize vasoreactivity in the high- and low-altitude pregnant guinea pigs or in their isolated aortic rings. We concluded that pregnancy at high compared with low altitude increased base-line SVR and aortic contractile sensitivity but that mechanisms other than decreased vasodilator prostaglandin production were responsible.     

鸡缺氧诱导因子-1[[alpha]]基因的差异表达与低氧适应性

低氧诱导因子-1(HIF-1)是在低氧的癌细胞中发现的一种转录激活因子, 在生物体氧平衡调节中起关键作用。藏鸡是对高原低氧、低温环境有着极强适应能力的高原土著品种, 相对而言, 白来航鸡和寿光鸡为两个低地鸡种。在常氧环境下对这3个鸡品种进行全期模拟低氧孵化, 结果显示, 藏鸡的孵化率显著高于两个低地鸡品种, 表现出了高度的耐受低氧环境的能力, 而对于低地鸡, 一定程度的低氧环境对其孵化是致命的。利用Taqman探针法FQRT-PCR技术检测了藏鸡、白来航鸡、寿光鸡HIF-1[[alpha]] 的组织特异性表达。结果表明, HIF-1[[alpha]] mRNA在3个鸡品种的大脑和骨骼肌组织均有表达, 并有明显的组织差异性, 脑的表达量最大; 并且发现常氧条件下孵化时, 藏鸡胚胎的大脑组织内HIF-1[[alpha]] 基因的表达量与低氧孵化的低地鸡胚胎相接近.     

Genetic adaptation to high altitude in the Ethiopian highlands

Background

Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.

Results

We have identified a set of candidate genes for positive selection in our high-altitude population sample, demonstrated significantly different hemoglobin levels between high- and low-altitude Ethiopians and have identified a subset of candidate genes for selection, several of which also show suggestive associations with hemoglobin levels.

Conclusions

We highlight several candidate genes for involvement in high-altitude adaptation in Ethiopia, including CBARA1, VAV3, ARNT2 and THRB. Although most of these genes have not been identified in previous studies of high-altitude Tibetan or Andean population samples, two of these genes (THRB and ARNT2) play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. These combined results suggest that adaptation to high altitude arose independently due to convergent evolution in high-altitude Amhara populations in Ethiopia.     

Developmental components of resting ventilation among high- and low-altitude Andean children and adults

This paper evaluates the age-associated changes of resting ventilation of 115 high- and low-altitude Aymara subjects, of whom 61 were from the rural Aymara village of Ventilla situated at an average altitude of 4,200 m and 54 from the rural village of Caranavi situated at an average altitude of 900 m. Comparison of the age patterns of resting ventilation suggests the following conclusions: 1) the resting ventilation (ml/kg/min) of high-altitude natives is markedly higher than that of low-altitude natives; 2) the age decline of ventilation is similar in both lowlanders and highlanders, but the starting point and therefore the age decline are much higher at high altitude; 3) the resting ventilation that characterizes high-altitude Andean natives is developmentally expressed in the same manner as it is at low altitude; and 4) the resting ventilation (ml/kg/min) of Aymara high-altitude natives is between 40–80% lower than that of Tibetans. Am J Phys Anthropol 109:295–301, 1999. © 1999 Wiley-Liss, Inc.     

The influence of altitude and topography on genetic structure in the long-toed salamander (Ambystoma macrodactulym)

A primary goal of molecular ecology is to understand the influence of abiotic factors on the spatial distribution of genetic variation. Features including altitudinal clines, topography and landscape characteristics affect the proportion of suitable habitat, influence dispersal patterns, and ultimately structure genetic differentiation among populations. We studied the effects of altitude and topography on genetic variation of long-toed salamanders (Ambystoma macrodactylum), a geographically widespread amphibian species throughout northwestern North America. We focused on 10 low altitude sites (< 1200 m) and 11 high-altitude sites in northwestern Montana and determined multilocus genotypes for 549 individuals using seven microsatellite loci. We tested four hypotheses: (1) gene flow is limited between high- and low-altitude sites; and, (2) gene flow is limited among high-altitude sites due to harsh habitat and extreme topographical relief between sites; (3) low-altitude sites exhibit higher among-site gene flow due to frequent flooding events and low altitudinal relief; and (4) there is a negative correlation between altitude and genetic variation. Overall F(ST) values were moderate (0.08611; P < 0.001). Pairwise F(ST) estimates between high and low populations and a population graphing method supported the hypothesis that low-altitude and high-altitude sites, taken together, are genetically differentiated from each other. Also as predicted, gene flow is more prominent among low-altitude sites than high-altitude sites; low-altitude sites had a significantly lower F(ST) (0.03995; P < 0.001) than high altitude sites (F(ST) = 0.10271; P < 0.001). Use of Bayesian analysis of population structure (BAPS) resulted in delineation of 10 genetic groups, two among low-altitude populations and eight among high-altitude populations. In addition, within high altitude populations, basin-level genetic structuring was apparent. A nonequilibrium algorithm for detecting current migration rates supported these population distinctions. Finally, we also found a significant negative correlation between genetic diversity and altitude. These results are consistent with the hypothesis that topography and altitudinal gradients shape the spatial distribution of genetic variation in a species with a broad geographical range and diverse life history. Our study sheds light on which key factors limit dispersal and ultimately species' distributions.     

Altitude, migration, and fertility in the Andes

In order to examine the relationship between hypoxia and reduced fertility of high Andean populations, a sample of 241 females living in the low-altitude Tambo Valley of Peru was studied. 63 of the subjects were born in the low-altitude valley, 121 were migrants from high altitudes, and 57 were migrants born in low altitudes. The rate of abortion was low among high-altitude subjects before they migrated, but became greater after migrating. It was found that the high-altitude populations had almost twice as long parity intervals than the low-altitude populations. Compared to migrants born at low altitudes, the high-altitude-born subjects who migrated to low altitudes had higher fertility rates. The results of the study are consistent with the hypothesis that high altitudes, through anoxia, have a lowering effect on fertility. Of the several possible explanations which might account for the increase in fertility of downward migrants on migration from high to low altitude (migration, socioeconomic factors, acculturation, seasonal male emigration from high altitude, and removal of hypoxia stress), altitude appears to be the most significant.     

Hypoxia-induced expression of HIF-1alpha and its target genes in umbilical venous endothelial cells of Tibetans and immigrant Han

The better adaptation of native Tibetans to hypoxia is thought to be partly due to improved umbilical circulation, which results in reduced pre- and postnatal fatalities. We hypothesized that the difference in umbilical circulation between native Tibetans and other high-altitude inhabitants was due to differences in the expression of hypoxia-induced factor (HIF-1) and its target genes vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). We tested this hypothesis by examining the effect of hypoxia on the expression of HIF-1alpha, VEGF, and iNOS in cultured umbilical venous endothelial cells (UVECs) from native Tibetans and immigrant Hans. UVECs were collected and cultured under hypoxic (0.5% oxygen) or normoxic conditions for 2, 4, 12 and 24 h. The mRNA levels of HIF-1alpha, VEGF, endothelial nitric oxide synthase (eNOS) and iNOS and the protein level of HIF-1alpha were determined with RT-PCR and Western blot analyses, respectively. In both immigrant Han and Tibetans, HIF-1alpha mRNA was constitutively expressed under normoxic condition, and remained constant after hypoxic exposure. In contrast, HIF-1alpha protein was undetectable under normoxic condition, but underwent dynamic changes in response to hypoxia. It was induced at 4 h, peaked at 12 h, and remained elevated at 24 h. Concurrent with the induction of HIF-1alpha protein, the mRNA levels of VEGF and iNOS were also up-regulated whereas that of eNOS was down-regulated. The lack of a hypoxia-related difference in the expression of HIF-1alpha and its target genes suggests that HIF-1alpha does not play a critical role in high altitude adaptation. Alternative mechanisms may be responsible for the better adaptation of native Tibetans.     

Long-Term Exposure to High Altitude Affects Conflict Control in the Conflict-Resolving Stage

The neurocognitive basis of the effect of long-term high altitude exposure on conflict control is unclear. Event related potentials (ERPs) were recorded in a flanker task to investigate the influence of high altitude on conflict control in the high-altitude group (who had lived at high altitude for three years but were born at low altitude) and the low-altitude group (living in low altitude only). Although altitude effect was not significant at the behavioral level, ERPs showed cognitive conflict modulation. The interaction between group and trial type was significant: P3 amplitude was greater in the low-altitude group than in the high-altitude group in the incongruent trial. This result suggests that long-term exposure to high altitude affects conflict control in the conflict-resolving stage, and that attentional resources are decreased to resist the conflict control in the high-altitude group.     

Stabilization of HIF-2α Induces sVEGFR-1 Production from Tumor-Associated Macrophages and Decreases Tumor Growth in a Murine Melanoma Model

Macrophage secretion of vascular endothelial growth factor (VEGF) in response to hypoxia contributes to tumor growth and angiogenesis. In addition to VEGF, hypoxic macrophages stimulated with GM-CSF secrete high levels of a soluble form of the VEGF receptor (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using mice with a monocyte/macrophage-selective deletion of hypoxia-inducible factor (HIF)-1α or HIF-2α, we recently demonstrated that the antitumor response to GM-CSF was dependent on HIF-2α-driven sVEGFR-1 production by tumor-associated macrophages, whereas HIF-1α specifically regulated VEGF production. We therefore hypothesized that chemical stabilization of HIF-2α using an inhibitor of prolyl hydroxylase domain 3 (an upstream inhibitor of HIF-2α activation) would increase sVEGFR-1 production from GM-CSF-stimulated macrophages. Treatment of macrophages with the prolyl hydroxylase domain 3 inhibitor AKB-6899 stabilized HIF-2α and increased sVEGFR-1 production from GM-CSF-treated macrophages, with no effect on HIF-1α accumulation or VEGF production. Treatment of B16F10 melanoma-bearing mice with GM-CSF and AKB-6899 significantly reduced tumor growth compared with either drug alone. Increased levels of sVEGFR-1 mRNA, but not VEGF mRNA, were detected within the tumors of GM-CSF- and AKB-6899-treated mice, correlating with decreased tumor vascularity. Finally, the antitumor and antiangiogenic effects of AKB-6899 were abrogated when mice were simultaneously treated with a sVEGFR-1 neutralizing Ab. These results demonstrate that AKB-6899 decreases tumor growth and angiogenesis in response to GM-CSF by increasing sVEGFR-1 production from tumor-associated macrophages. Specific activation of HIF-2α can therefore decrease tumor growth and angiogenesis.     

Regulation of breathing in newborns at high altitude

Resting respiratory parameters and respiratory responses to acute changes in end-tidal O2 and CO2 pressure (PETO2 and PETCO2) were investigated in Peru in 23 newborn and 4 older infants at 3.850 m and in 13 newborns at 800 m. The study was done with the subjects asleep in a thermoneutral environment. The transient increase in ventilation in both high- and low-altitude newborns was followed by a decrease in response to acute hypoxia. During hyperoxia the two groups showed a slight but not clearly significant decrease in ventilation, whereas older high-altitude infants showed a sustained decrease. All subjects showed a prompt and clear response to CO2 inhalation during hyperoxia. We conclude that ventilatory peripheral chemoreflex is not fully developed in newborns regardless of altitude. The weak link in the reflex arc may reside in the afferent component because CO2 response was not impaired. Since hypoxic response became persistent in older infants its blunting in adult high-altitude natives is not a legacy of newborns.     

Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness.

Vascular endothelial growth factor (VEGF) is a hypoxia-induced protein that produces vascular permeability, and limited evidence suggests a possible role for VEGF in the pathophysiology of acute mountain sickness (AMS) and/or high-altitude cerebral edema (HACE). Previous studies demonstrated that plasma VEGF alone does not correlate with AMS; however, soluble VEGF receptor (sFlt-1), not accounted for in previous studies, can bind VEGF in the circulation, reducing VEGF activity. In the present study, we hypothesized that free VEGF is greater and sFlt-1 less in subjects with AMS compared with well individuals at high altitude. Subjects were exposed to 4,300 m for 19-20 h (baseline 1,600 m). The incidence of AMS was determined by using a modified Lake Louise symptom score and the Environmental Symptoms Questionnaire for cerebral effects. Plasma was collected at low altitude and after 24 h at high altitude, or at time of illness, and then analyzed by ELISA for VEGF and for soluble VEGF receptor, sFlt-1. AMS subjects had lower sFlt-1 at both low and high altitude compared with well subjects and a significant rise in free plasma VEGF on ascent to altitude compared with well subjects. We conclude that increased free plasma VEGF on ascent to altitude is associated with AMS and may play a role in pathophysiology of AMS.     

Chronic propranolol treatment blunts right ventricular hypertrophy in rats at high altitude

Chronic beta-receptor blockade has been reported to inhibit right ventricular hypertrophy in rats at high altitude. If so, we wanted to determine whether beta-receptor blockade or some other drug action were involved and whether the heart, the lung vessels, or blood alterations were affected. In rats, chronic treatment with DL-propranolol (2 mg/kg ip once daily) reduced right ventricular hypertrophy and polycythemia of chronic high altitude. D-Propranolol and metoprolol did not reduce hypoxia-induced right ventricular hypertrophy or polycythemia. In isolated lungs from low-altitude rats treated chronically with DL-propranolol or with D-propranolol the pressor response to acute hypoxia was blunted. Chronic DL-propranolol blunted the acute hypoxic pressor response and angiotensin II induced vasoconstriction in lungs from high-altitude rats. Two effects of DL-propranolol treatment were seen: 1) blockade of beta 2-adrenergic receptors, which reduced the right ventricular hypertrophy of high altitude through reduction of hematocrit; and 2) a non-beta-effect, which reduced vascular responsiveness to acute hypoxia in the isolated lung preparation.     

Chronotype preferences of college students from varied altitude backgrounds in Ethiopia

ABSTRACT

The purpose of this study was to compare chronotype preferences of college students from high- and low-altitude backgrounds living in a tropical setting of Ethiopia. Chronotype (morningness–eveningness) is a preference for a given time of day for physical or mental activities. The present cross-sectional study employed Horne and Osteberg Morningness-Eveningness Questionnaires to evaluate chronotype preferences. The chronotype preference of 264 male college students from varied altitude backgrounds indicated significant differences (p < 0.001). Our findings confirm our hypothesis, of the prevalence of M-types dominant chronotype among college students at low than high altitude. However, we did not confirm our second hypothesis, since students from high-altitude backgrounds were generally I-type dominant chronotype. Similarly, students’ academic performances from low- compared to high-altitudes backgrounds also indicated significant differences (p < 0.003). Better academic performances were seen in students with I-type chronotype orientations from high altitudes.     

Blood rheology in acute mountain sickness and high-altitude pulmonary edema.

The role of blood rheology in the pathogenesis of acute mountain sickness and high-altitude pulmonary edema was investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, were studied at low altitude (490 m) and at 2 h and 18 h after arrival at 4,559 m. Eight subjects remained healthy, seven developed acute mountain sickness, and eight developed high-altitude pulmonary edema. Hematocrit, whole blood viscosity, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability (filtration) were measured. Plasma viscosity and erythrocyte deformability remained unaffected. The hematocrit level was lower 2 h after the arrival at high altitude and higher after 18 h compared with low altitude. The whole blood viscosity changed accordingly. The erythrocyte aggregation was about doubled 18 h after the arrival compared with low-altitude values, which reflects the acute phase reaction. There were, however, no significant differences in any rheological parameters between healthy individuals and subjects with acute mountain sickness or high-altitude pulmonary edema, either before or during the illness. We conclude that rheological abnormalities can be excluded as an initiating event in the development of acute mountain sickness and high-altitude pulmonary edema.     

A Study of High-Altitude Hypoxia-Induced Cell Stress in Murine Model

We evaluated the effects of high-altitude hypoxic stress in the murine model. For this purpose, 36 CR-mice in group A were maintained at the altitude of 3,820?m for hypoxia-induced factor (HIF)-1?? expression analysis by immunohistochemistry. The 36 Wistar rats in group B were maintained in low-pressure (400?C420?kPa) oxygen chamber, and the effects of hypoxia on myocardial mitochondria were studied. In the 36 CR-mice of group C, plasma vascular endothelial growth factor (VEGF) levels were determined using strept?Cavidin?Cbiotin complex/diaminobenzidine method after exposure to different altitudes/O₂-concentrations. The data show that in experimental group A1, endothelin (ET)-1?? concentrations gradually increased whereas HIF-1?? expression in myocardial cells was higher (P?<?0.01) than in control group A2. In rats of group B, the myocardial mitochondria numbers were reduced during the initial phase of acute stress response to hypoxia and cellular injury but, later, mitochondrial numbers were restored to normal values. In mice of experimental group C1, plasma VEGF concentrations increased under hypoxia, which were significantly higher (P?<?0.01) than those of control group C2. We, therefore, concluded that high-altitude hypoxia: (i) induced HIF-1?? expression; (ii) prompted adaptation/acclimatization after initial stress and cellular injury; and (iii) enhanced VEGF expression in murine.