| In recent years,the number of lowlanders who need to work and stay in high-altitude areas for several months or years has increased because of commercial activities or military operations.Compared with permanent residents,sojourners living at high altitudes experience more challenges.One of the most serious problems that individuals chronically exposed to hypoxia may suffer from is high-altitude pulmonary hypertension(HAPH).HAPH is a progressive disease that results in right heart dysfunction and is associated with poor prognosis.The hallmarks of HAPH include impaired pulmonary vasoreactivity and increased muscularisation of distal pulmonary vessels.Therefore,a clear understanding about the mechanisms of vascular remodeling may lead to the development of novel therapeutic approaches for the prevention and/or treatment of HAPH.Current treatments for HAPH involve lowering the altitude to increase oxygen supply and administering pharmacological drugs,including prostanoids,endothelin receptor blockers,and phosphodiesterase-5 inhibitors.These pharmacological treatments mainly focus on reversing the abnormal arterial remodeling.However,these medications are not sufficient to totally regress vascular remodeling and prevent right heart dysfunction due to the multiple mechanisms involved in arterial remodeling after hypoxia.Therefore,the development of more effective prevention and treatment options against HAPH remains the primary focus.The best way to prevent hypoxia-induced diseases is to relieve individuals from hypoxia.In aviation physiology,oxygen supply based on physiological equivalent altitude is one of the main ways to prevent the effects of hypoxia.According to this principle,when the inspired oxygen concentration is 42%at 5000 m,the physiological equivalent altitude is about sea level.A previous work in our laboratory confirmed that rats staying at 5000 m in a hypobaric chamber for 2 weeks did not experience growth inhibition or cardiovascular dysfunction as long as their oxygenation levels were equivalent to the one at sea level.However,maintaining the inspired oxygen concentration at approximately 42%at 5000 m all day for individuals staying in high-altitude areas is impractical and uneconomical.Our previous work suggested another possible and effective method to prevent HAPH,which consisted of short-duration reoxygenation.Specifically,we used the hindlimb unweighting rat model to explore the effect of simulated weightlessness on the cardiovascular system.The results indicated that the arteries of rats underwent regional specific remodeling to simulated weightlessness;in the vascular beds of the lower body,resistance vessels exhibited hypotrophy,decreased myogenic tone and vasoreactivity.On the contrary,cerebral arteries exhibited hypertrophy and an increase in vasoreactivity as a result of adaptation to cerebral hypertension.In subsequent mechanism studies,we also found that the underlying mechanisms included ion channels,contractile proteins and contractile regulatory proteins,the local renin-angiotensin system,the nitric oxide pathway,intracellular calcium,inflammation,oxidative stress,etc.However,the key mechanism remains uncertain.In the study of countermeasures against the effects of weightlessness,we observed that 1 h of intermittent artificial gravity(1 h of restoring to normal posture)daily prevented the remodeling of some arteries caused by 23 h of simulated microgravity..In the study,we observed that 1 h of intermittent artificial gravity(1 h of restoring to normal posture)daily prevented the remodeling of some arteries caused by 23 h of simulated microgravity.Inspired by that arterial memory effect in above work,we believe that the mechanism that mediates arterial remodeling induced by high-altitude hypoxia is similar to that in the previous simulated weightlessness rat model and the arterial culture model to some extent.Firstly,before entering the abnormal environment,the organism exhibits no factors that could contribute to arterial remodeling;the remodeling is only caused by the abnormal physical or chemical environment.Secondly,the initiating factors in arterial remodeling include hemodynamic changes.Therefore,we hypothesize that the phenomenon of intermittent short-duration restoration to normal physical and/or chemical environment to reverse arterial remodeling may also exist in pulmonary arterial remodeling induced by high-altitude hypoxia.Furthermore,previous studies reported that frequent oxygen inhalation alleviated the symptoms in residents living at high altitudes.However,these studies focused more on relieving the symptoms of acute or chronic mountain sickness rather than paying attention to the development of pulmonary arterial remodeling disease.Moreover,research focusing on the relationship between protective effect and reoxygenation level,frequency,or oxygen saturation is lacking.In this study,we used a hypobaric chamber to simulate 5000-m altitude hypoxia.By changing the gas composition in the chamber based on the physiological equivalent altitude,we observed whether daily short-duration reoxygenation at sea level could prevent pulmonary hypertension caused by 5000-m altitude exposure for 2 weeks in rats.The main findings of the current study are as follows:1.Daily intermittent but not continuous 3-h reoxygenation at sea level partially prevented hypoxia-induced HAPH.(1)Simple hypobaric exposure did not affect the pulmonary arterial pressure and right ventricular(RV)structure;(2)Daily 3-h intermittent reoxygenation significantly reduced the levels of hematocrit and right ventricular systolic pressure(RVSP).(3)Daily 3-h intermittent reoxygenation significantly prevented RV hypertrophy.(4)Daily 3-h continues reoxygenation did not have obvious effect on the above changes.2.Intermittent short-duration reoxygenation prevents functional and structural remodeling of pulmonary arteries under hypoxia.(1)Intermittent short-duration reoxygenation prevented functional remodeling of pulmonary arteries under hypoxia;①Intermittent short-duration reoxygenation improved the impaired vasodilatory responses elicited by ACh,SNP,and NS 1619;②Intermittent short-duration reoxygenation improved vasoconstrictions dependent on KCl,PE or U-46619.(2)Intermittent short-duration reoxygenation prevented structural remodeling of pulmonary arteries under hypoxia;①Intermittent short-duration reoxygenation attenuated the increase in the degree of muscularization pulmonary vessels(Diameter:25-75 μm)under hypoxia;②Intermittent short-duration reoxygenation attenuated the enhanced wall thickness of arterioles(Diameter:50-200 μm)induced by hypoxia;③Intermittent short-duration reoxygenation attenuated the ratio of Ki67-positive arteries(Diameter:50-200 μm)and VEGF expression under hypoxia;④Intermittent short-duration reoxygenation prevents proliferation and migration enhancement,apoptosis resistance and phenotype conversion of human pulmonary artery smooth muscle cells(HPASMCs)under hypoxia.(3)The genes and pathways involved in preventing the high-altitude pulmonary arterial remodeling effect induced by intermittent short-duration reoxygenation were investigated by RNA-seq,resulting in a list of potential targets for preventing HAPH.3.An optimal combination of different reoxygenation factors,such as intermittent reoxygenation level,frequency,and duration,may exist.(1)Increasing the frequency of reoxygenation did not further decrease RVSP and RV hypertrophy;(2)Increasing the frequency of reoxygenation did not further improve pulmonary arterial remodelling under hypoxia;(3)Increasing the frequency and total time of reoxygenation augments oxidative stress in the lungs under hypoxia.In conclusion,daily intermittent short-duration reoxygenation at sea level partially prevents pulmonary arterial remodeling and thus alleviates pulmonary hypertension in SD rats exposed to 5,000-m hypoxia.Investigation of genes and pathways involved in the prevention of the high-altitude pulmonary arterial remodeling effect induced by intermittent short-duration reoxygenation provides potential targets for preventing HAPH.Finally,by increasing the frequency and total time of intermittent reoxygenation,HAPH is not further attenuated,which is likely attributed to augmented oxidative stress.However,an optimal combination of intermittent reoxygenation physiological altitude,frequency,and duration can be determined and needs further exploration. |
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