Vascular homeostasis at high‐altitude: role of genetic variants and transcription factors

Abstract

total number of manuscript pages -41 • total number of figures -4 • word count for the body of the text -7834 • type of contribution -review article AbstractHigh-altitude pulmonary edema (HAPE) occurs most frequently in non-acclimatized low landers on exposure to altitude ≥2500m. HAPE is a complex condition that involves perturbation of signaling pathways in vasoconstrictors, vasodilators, anti-diuretics and vascular growth factors. Genetic variations are instrumental in regulating these pathways and evidence is accumulating for a role of epigenetic modification in hypoxic responses. This review focuses on the crosstalk between HAPE-associated genetic variants and transcription factors, comparing high-altitude adapted and HAPE-afflicted subjects. This approach might ultimately yield biomarker information both to understand and to design therapies for high altitude adaptation.Evolution and physiological adaptation have permitted survival at the highest topographically elevated regions of the world. [1][2][3][4][5] Reduced air pressure at high-altitude decreases the partial pressure of inspired oxygen, affecting lungs, brain, heart and blood and can lead to a spectrum of high-altitude disorders including high-altitude pulmonary edema (HAPE), acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). 6,7 This review focuses on HAPE. HAPE is a consequence of hypoxic pulmonary vasoconstriction leading to increased pulmonary arterial pressure and capillary stress failure. 8-11 HAPE victims have lower arterial oxygen saturation (SaO2) and higher heart rate, pulmonary vascular resistance and pulmonary vascular resistance index 12,13 than do unaffected sojourners to altitude. Clinically HAPE is characterized by dyspnoea, elevated body temperature, pink frothy sputum, tachypnoea, tachycardia, persistent cough and cyanosis. [14][15][16][17] Chest X-rays and CT scans show increased lung vascular markings and patchy shadows. 18,19 There have been great strides in understanding the clinical and physiological mechanisms of HAPE that has led to the discovery of successful treatments. Information on genetic contributions to this disorder has also grown rapidly over the last decade, partly to the development and implementation of newer genetic techniques. Candidate-gene approaches, advanced techniques such as Next-GenerationSequencing and Genome-Wide Association Studies have led to association of multiple genetic variants with high-altitude adaptation or maladaptation. [20][21][22][23][24][25][26] The majority of these genes belong to multiple, frequently related pathways. These include the renin-angiotensin aldosterone system, apelin signaling, nitric oxide signaling, and hypoxia induced signaling.These pathways regulate vasoactive molecules including angiotensin II, apelin, nitric oxide, aldosterone, and beta-adrenergics. [27][28][29][30][31] In addition to genetic variation, epigenetics plays prominent role in HAPE and other diseases. [32][33][34][35] DNA methylation, acetylation, histone modifications/chromatin rem...

Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure

“…In this study, men had greater increases in SBP, and women had greater increases in DBP and HR at HA. These data are in agreement with previous studies ( Reckelhoff, 2001 ; Boos et al, 2017 ; Horiuchi et al, 2019 ) looking at the perturbation of signaling pathways at HA, including vascular, anti-diuretic, and vascular growth factors ( Mishra et al, 2015b ; Richalet, 2016 ; Chanana et al, 2020 ). The HA-associated increase in pulmonary pressure was comparatively more in women than in men.…”

“…Pulmonary hypertension (PH) is characterized by vascular remodeling caused by abnormal smooth muscle production and increased pulmonary arteriolar resistance, depleted bioavailability of vasodilators such as nitric oxide (NO), and enhanced vasoconstrictors ( Naeije, 2010 ; Chanana et al, 2020 ). PH can result from acute hypoxia and chronic exposure to high-altitudes.…”

Morphological and functional findings in COVID-19 lung disease as compared to Pneumonia, ARDS, and High-Altitude Pulmonary Edema

“…The pathophysiology of HAPE involves a reduced environmental partial pressure of inspired oxygen causing hypoxic pulmonary vasoconstriction that leads to an increased pulmonary arterial pressure with focalized higher pulmonary vascular resistances, higher heart rate and lower arterial oxygen saturation ( Chanana et al, 2020 ). The etiopathology of HAPE is not clear and several hypothesis have been described: 1) genetic predisposition; 2) changes in renin-angiotensin-aldosterone system (RAS), since aldosterone increases the retention of extracellular fluid ( Chanana et al, 2020 ); 3) modifications in nitric oxide (NO), which usually maintains the pulmonary vascular homeostasis; 4) different expression of hypoxia-inducible factor (HIF)-1 that exponentially increases when the cellular oxygen is low ( Chanana et al, 2020 ); 5) viral infection which may explain the similar pattern observed in COVID-19 pneumonia ( Zubieta-Calleja, 1989 ). The tongue in HAPE has very similar characteristics to the tongue in COVID-19.…”

“…The tongue in HAPE has very similar characteristics to the tongue in COVID-19. Clinical symptoms of HAPE include dyspnea, frothy pink sputum, tachypnea, persistent cough, cyanosis, and tachycardia ( Chanana et al, 2020 ). The clinical diagnosis of HAPE is based on the presence of breathlessness, cough, chest discomfort and headache along with tachycardia, tachypnea, and a SpO 2 < 86% for an altitude of 3500 m in a patient arriving to high altitude within up to 5 days.…”

Effects of Plateau Air Quality and Low Oxygen Content on Platelet mtDNA Methylation and High Altitude Pulmonary Edema

“…Mitochondria may be the core element for HA adaptation and altitude sickness, and mtDNA mutations may be associated with the occurrence of HAPE. Previous studies have found that mitochondrial epigenetics might play an important role in HAPE apart from genetic variation (Chanana et al, 2020). ROS is mainly generated by the mitochondrial electron transport chain complexes (McElroy and Chandel, 2017).…”