Effects Of High Altitude Hypoxia Exposure On Blood Pressure And Its Mechanisms

ObjectiveCurrent epidemiological investigation shows that hypoxia environment can lead to abnormal blood pressure,among which altitude-related hypertension（ARH）is relatively common.Weighted gene coexpression network analysis found that mi R-182-5p was the core nodes in the hypertension-related mi RNA-gene network,and hypoxia inducible factor 1α（HIF-1α）is the target gene of mi R-182-5p.So it may be involved in the regulation of blood pressure under hypoxia.The main purpose of this study is to investigate the change pattern of blood pressure under chronic hypoxia exposure,exploring the molecular mechanism of mi R-182-5p involved in the phenotypic transformation of vascular smooth muscle cells under hypoxia and try to clarify the possible pathogenesis of ARH.Methods1987 hypertensive patients were enrolled for the research.According to the diagnostic criteria and inclusion procedures of ARH,the patients were divided into ARH group and essential hypertension（EH）group.The clinical data of the two groups were compared and the clinical characteristics of ARH were analyzed.SD rats were placed in a hypobaric chamber simulated altitude of 5000 m（PB 404 mm Hg,PO₂84mm Hg）for 24 weeks.The change pattern of blood pressure under hypoxia was observed.Blood samples were retained for the determination of the biochemical markers and vasoactive substances.The remodeling of the tertiary branch vessels of superior mesenteric artery were observed by hematoxylin-eosin staining（HE staining）and the expression level ofα-SMA were detected by immunohistochemistry staining.To clarify the molecular mechanisms of vascular remodeling and phenotypic switching of smooth muscle cells under hypoxia,rat aortic smooth muscle cells（RASMCs）were cultured in hypoxia.The mi R-182-5p expression under hypoxia exposure and effect on phenotype marker protein expression were observed by RT-q PCR and Western Blot and dual luciferase reporter assay determined the targeting relationship between mi R-182-5p and G protein signaling regulator 5（RGS5）.ResultsARH can occur both in Han immigrants and Tibetan natives,and more common in Han immigrants.Compared with EH,ARH has predominant increase in diastolic blood pressure（DBP）,which accompanied by increased red blood cell（RBC）,hemoglobin,hematocrit and uric acid（P<0.01）.Also the ARH had more significant structural changes in the right heart,including the right atrium and right ventricular enlargement（P<0.01）.There was no statistical difference in the target organ damage between the two groups（P>0.05）.Multivariate Logistic regression analysis showed that male,Han nationality,height of residence,elevated hemoglobin and uric acid,and obesity were risk factors for ARH.The hypoxia exposure simulated 5000 m caused increased blood pressure in SD rats,with the most predominant increase in second week.The blood pressure gradually stabilized with prolonged exposure to hypoxia,but higher than control during the whole observation period（P<0.05）.The levels of RBC,hemoglobin and hematocrit increased with hypoxia exposure.The level of epinephrine,norepinephrine,renin,angiotensinⅡ,aldosterone,and endothelin-1,as well as nitric oxide were increased in hypoxia and the most significant elevation were observed in the second week（P<0.05）,while the levels of blood glucose,LDL cholesterol,HDL cholesterol and total cholesterol were unchanged（P>0.05）.Total peripheral resistance was increased at the end of experiment under hypoxia exposure（P<0.05）.HE staining showed thickened vascular walls and reduced lumen of the superior mesenteric artery tertiary branch vessels in the H 24W group,also the ratio of medial area/luminal area was increased at the end of 24 W hypoxia exposure compared with control group（P<0.01）.Immunohistochemical staining revealed diminishedα-SMA expression in the vascular wall under hypoxia.In cells transfected with the p CMV-RGS5-WT（OE-RGS5）plasmid,mi R-182-5p mimic significantly reduced luciferase activity compared with mimic NC（P<0.01）,indicating that mi R-182-5p can target RGS5 3’-UTR and reduce RGS5 gene expression.Under hypoxia,the expression of mi R-182-5p increased,accompanied by decreased expression ofα-SMA,SMMHCs,RGS5,Rho A activity,protein expressions of Rho A and p-MYPT 1,while the expression of CK8,CK18.Increased.The most significant alterations were observed at 48 h in hypoxia（P<0.01）.The rescue experiment found that overexpression of RGS5 could reverse these results（P<0.01）.ConclusionsLong-term hypoxia exposure can cause the increase of blood pressure in humans and rats.ARH is mostly common in the plain immigrants,but also occurs in the high altitude natives,often accompanied with erythrocytosis,right heart enlargement.Risk factors include:male,Han nationality,residence altitude,hemoglobin and uric acid increase,obesity.In the early stage of hypoxia exposure,blood pressure increase may be related to disturbed neuroendocrine regulation,while the maintenance of high levels of blood pressure under prolonged exposure to hypoxia may be related to vascular remodeling caused by RASMCs phenotype switching.The mechanism may be that upregulation of mi R-182-5p under hypoxia targets and negatively regulates RGS5 gene,suppressing Rho A signaling,leading to downregulation of intracellularα-SMA and SMMHCs expression,and ultimately promotes the transformation of RASMCs from contractile phenotype to synthetic phenotype.