Adventitial Alterations Are the Main Features in Pulmonary Artery Remodeling due to Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats

Abstract

Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, n = 10). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer.

Chronic Intermittent Hypobaric Hypoxia (4600 M) Attenuates Pulmonary Vasodilation Induced by Acetylcholine or Sodium Nitroprusside

“…However, nicootinamide adenine dinucleotide phosphatase oxidase plays a crucial role in eNOS uncoupling since it produces reactive oxygen species (Cuzzocrea et al, 2004;Norton et al, 2013). Intolerant rats exposed to CIHH displayed increased O 2 and decreased NO (Siqués et al, 2014;Brito et al, 2015;Lüneburg et al, 2016). In agreement with these studies, our intolerant rats have low NOx levels and a low vascular response to Ach.…”

“…An additional possibility is that CH increases the sensitivity of the contractile apparatus to Ca +2 and mediates this response via activation of the RhoA/Rho kinase (ROK) pathway, and consequently inhibits the myosin light-chain phosphatase, a central component of vascular smooth muscle contraction ( Jernigan and Resta, 2014). However, our study corroborated decreased NOx levels in intolerant animals during CIHH (Siqués et al, 2014;Brito et al, 2015), which could partially explain the increased potassium R MAX .…”

“…Another mechanism that reduces NO bioavailability is an increased concentration of free radicals, such as the superoxide anion (O 2 -). In fact, rats exposed to CIHH displayed increased O 2 and decreased NO (Siqués et al, 2014;Brito et al, 2015), supporting the adventitia's role in O 2 production. However, vascular function and its link with NO levels in animals exposed to CIHH have not been studied.…”

Long-Term Intermittent Work at High Altitude: Right Heart Functional and Morphological Status and Associated Cardiometabolic Factors

“…Some studies in humans have demonstrated changes in the right heart circulation that are similar to those occurring in CH, such as a rise in PAP and right ventricular enlargement and/or hypertrophy (Richalet et al, 2002 ; Sarybaev et al, 2003 ; Brito et al, 2007 ). Remodeling of pulmonary vessels has also been demonstrated in animal models (Brito et al, 2015 ). Notwithstanding, there is scarce research assessing these changes over long durations in larger groups of individuals or looking for new potential associations with other physiological and biochemical variables as associated factors.…”

Current insights into the molecular mechanisms of hypoxic pre- and postconditioning using hypobaric hypoxia

“…Currently it is well-established that adaptation (acclimatization) to high altitude both of natural origin and simulated in the hypobaric chamber has a number of beneficial effects on human health, whole body hypoxic tolerance and improvement of physical training (Meerson, 1984 ; Meerson et al, 1996 ; Millet et al, 2013 ). These effects are observed under conditions of chronic mild hypobaric hypoxia (acclimatization mode) and result from reprogramming of the cardio-pulmonary and metabolic processes, including erythropoiesis, vascular remodeling, pulmonary changes and cardiac hypertrophy (Hultgren and Miller, 1967 ; Savourey et al, 2004 ; Brito et al, 2015 ). The integrity of these reactions is called systemic “structural trace of adaptation” due to which the resistance of an organism against any forthcoming hypoxic exposures is achieved along with more general protective effects (Meerson, 1984 ).…”