Backward and in Heels . . . Mabel Purefoy FitzGerald's Extraordinary Journey to Discovery at High Altitudes.

In 1911, Mabel Purefoy FitzGerald (1872-1973) conducted a study in the mountains of Colorado that offered invaluable insights into how the body responds to chronic hypoxia. Researchers awarded the Nobel Prize for Physiology or Medicine 2019 cited her work as critical in unravelling the hypoxia sensing system. The astounding career situation in which FitzGerald found herself while conducting this study offers important insights into the challenges faced by women in science at the turn of the twentieth century.

Identification of a miRNA-mRNA Regulatory Networks in Placental Tissue Associated With Tibetan High Altitude Adaptation.

The Tibetan population has lived and successfully reproduced at high altitude for many generations. Studies have shown that Tibetans have various mechanisms for protection against high-altitude hypoxia, which are probably due, at least in part, to placental adaptation. However, comprehensive analyses of placentas in Tibetans are lacking.

Enhanced Placental Mitochondrial Respiration in Tibetan Women at High Altitude.

Living at high altitudes is extremely challenging as it entails exposure to hypoxia, low temperatures, and high levels of UV radiation. However, the Tibetan population has adapted to such conditions on both a physiological and genetic level over 30,000-40,000 years. It has long been speculated that fetal growth restriction is caused by abnormal placental development.

Protective Effects from the Ischemic/Hypoxic Stress Induced by Labor in the High-Altitude Tibetan Placenta.

Labor and vaginal delivery cause acute ischemic/hypoxic insult to the placenta. Previous studies demonstrate that placentas from high altitude non-natives showed blunted responses to ischemic/hypoxic insult caused by labor and vaginal birth, and there were some differences in the ATP/ADP production ratio. We hypothesized that adapted highlanders would not have a stress response to the acute hypoxia/ischemia of labor.

PP018. Does altitude affect the placental renin angiotensin system (RAS) in pre-eclampsia (PE)?

Introduction: We have previously shown the activation of placental RAS in high altitude normotensive (NT) pregnancies [1], presumably related to hypoxia during placental development. PE incidence is increased at high altitude; hypoxia-reoxygenation injury contributes to the elevated oxidative stress seen in this condition. Binding of Angiotensin II to its type I receptor (AT1R) increases generation of reactive oxygen species and we have shown an increase in AT1R in PE [2].

Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA-210 and protein synthesis inhibition.

Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms.

Cross talk between S-nitrosylation and S-glutathionylation in control of the Na,K-ATPase regulation in hypoxic heart.

Oxygen-induced regulation of Na,K-ATPase was studied in rat myocardium. In rat heart, Na,K-ATPase responded to hypoxia with a dose-dependent inhibition in hydrolytic activity. Inhibition of Na,K-ATPase in hypoxic rat heart was associated with decrease in nitric oxide (NO) production and progressive oxidative stress.

Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude.

Pregnancy at high altitude is associated with a reduction in birth weight of ∼100 g/1000 m of ascent. The underlying mechanisms are unclear but may involve alteration in energy-demanding activities, such as protein synthesis. To test this hypothesis, both in vivo and in vitro approaches were used.

Human placental metabolic adaptation to chronic hypoxia, high altitude: hypoxic preconditioning.

We have previously demonstrated placentas from laboring deliveries at high altitude have lower binding of hypoxia-inducible transcription factor (HIF) to DNA than those from low altitude. It has recently been reported that labor causes oxidative stress in placentas, likely due to ischemic hypoxic insult. We hypothesized that placentas of high-altitude residents acquired resistance, in the course of their development, to oxidative stress during labor.

The neuronal control of hypoxic ventilation: erythropoietin and sexual dimorphism.

Using mice, we demonstrated that when oxygen supply is lowered, erythropoietin (Epo), the main regulator of red blood cell production, modulates the ventilatory response by interacting with central (brainstem) and peripheral (carotid bodies) respiratory centers. We showed that enhanced Epo levels in the brainstem increased the hypoxic ventilatory response, and that intracerebroventricular injection of an Epo antagonist (soluble Epo receptor) abolished the ventilatory acclimatization to hypoxia. More recently, we have found that the impact of Epo on ventilation occurs in a sex-dependent manner.

Ginkgo biloba does--and does not--prevent acute mountain sickness.

Objective: To determine the efficacy of 2 different sources of Ginkgo biloba extract (GBE) in reducing the incidence and severity of acute mountain sickness (AMS) following rapid ascent to high altitude.

Methods: Two randomized, double-blind, placebo-controlled cohort studies were conducted in which participants were treated with GBE (240 mg x d(-1)) or placebo prior to and including the day of ascent from 1600 m to 4300 m (ascent in 2 hours by car). Acute mountain sickness was diagnosed if the Environmental Symptom Questionnaire III acute mountain sickness-cerebral (AMS-C) score was > or =0.

Enhanced leukocyte HIF-1alpha and HIF-1 DNA binding in humans after rapid ascent to 4300 m.

Hypoxia plays a crucial role in the pathogenesis of a multitude of diseases and clinical conditions such as cancer, diabetes, cardiovascular disease, stroke, pulmonary disease, inflammation, organ transplant, and wound healing. Investigations into the role of hypoxia-inducible transcription factor (HIF) in disease development have been conducted with the basic premise that HIF is activated in vivo during hypoxia in humans, yet this basic physiologic premise has never verified. Thus, we hypothesized that HIF-1 DNA binding would be enhanced in vivo in humans in response to acute global hypoxia.

Competitive substrates for P-glycoprotein and organic anion protein transporters differentially reduce blood organ transport of fentanyl and loperamide: pharmacokinetics and pharmacodynamics in Sprague-Dawley rats.

Background: Drug transport proteins may be instrumental in controlling the concentration of fentanyl at mu receptors in the brain and may provide potential therapeutic targets for controlling an individual response to opioid administration. P-glycoprotein (P-gp) efflux transporter and organic anion transport protein inward transporters (OATP, human; Oatp, rat) have been implicated in fentanyl and verapamil (only P-gp) transport across the blood-brain barrier. We hypothesized that transport proteins P-gp and Oatp mediate opioid uptake in a drug and organ-specific manner, making them excellent potential targets for therapeutic intervention.

Ventilatory responses to acute and chronic hypoxia are altered in female but not male Paskin-deficient mice.

Proteins harboring a Per-Arnt-Sim (PAS) domain are versatile and allow archaea, bacteria, and plants to sense oxygen partial pressure, as well as light intensity and redox potential. A PAS domain associated with a histidine kinase domain is found in FixL, the oxygen sensor molecule of Rhizobium species. PASKIN is the mammalian homolog of FixL, but its function is far from being understood.

Hypoxia and placental remodelling.

In the first trimester of pregnancy fetal trophoblast cells invade the maternal uterine spiral arteries leading to loss of the vascular cells from the vessel wall and remodelling of the extracellular matrix. This is crucial to ensure that sufficient blood can reach the developing fetus. Impaired arterial remodelling is a feature of the major pregnancy pathologies pre-eclampsia and fetal growth restriction.

Metabolic markers of hypoxia: systems biology application in biomedicine.

ABSTRACT The overall goal of this review is to provide insight into methodologies for 'omic investigations and hypoxic biomarkers that have been identified using 'omic techniques. First, a detailed description of current metabolomic, proteomic, and genomic technologies is provided, followed by a basic introduction to biostatistics and how to interpret 'omic data. Metabolomic biomarkers of diseases in which hypoxia plays a role are then reviewed by those that involved chronic (pulmonary disease, cardiovascular disease, cancer) and acute (stroke, myocardial infarction, ischemia) hypoxia.

Acute hypobaric hypoxia (5486 m) induces greater pulmonary HIF-1 activation in hilltop compared to madison rats.

Compared to Madison strain Sprague-Dawley rats, the Hilltop strain is resistant to acute hypoxic pulmonary vasoconstriction and pulmonary leak, a pathology resembling high altitude pulmonary edema (HAPE) in humans. Hypoxia inducible transcription factor-1 (HIF-1) mediates transcription of proteins that can "rescue" tissue from hypoxia, including vasoactive and angiogenic proteins such as inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF). Because these proteins have theoretical relevance to the etiology of HAPE, we hypothesized that hypoxia-resistant Hilltop rats acutely exposed to high altitude would have greater HIF-1 activity and expression of iNOS and VEGF as compared to hypoxia-sensitive Madison rats.

Neutral endopeptidase null mice are less susceptible to high altitude-induced pulmonary vascular leak.

Hypoxia increases pulmonary vascular leak, which is regulated in part by neutral endopeptidase (NEP). NEP is a cell-surface metalloprotease that degrades several vasoactive peptides, including endothelin-1 (ET-1) and atrial natriuretic peptide (ANP). We therefore hypothesized that NEP attenuates high altitude-induced pulmonary vascular leak.

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.