A Study On The Role Of HIF-1α-ATF-4/VEGF-A Pathways In SAH-induced Retinal Hypoxia

[Background] Almost all multicellular organisms generate energy in the form of adenosine triphosphate(ATP)through the consumption of oxygen.The cells become unable to function properly when supply less oxygen to the tissues.The oxygen sensing system(OSS)can always be highly sensitive to the change of oxygen concentration in the body.Once a hypoxia state of cells,the OSS will act,so that a good deal of hypoxia-related genes activation,including vascular endothelial growth factor(VEGF)and erythropoietin(EPO).And finally,the activation of these hypoxia-related genes increases cells’ ability to survive in hypoxia condition.Hypoxia-inducible factor(HIF)can control the expression of majority hypoxiarelated genes.Deferoxamine(DFO)has a function to promote the growth of blood vessels and reduce oxygen consumption and state of hypoxia.Subarachnoid hemorrhage(SAH)as a cerebrovascular accident is associated with high rates of disability and mortality.In recent years,along with the improvement of medical technology,quality of life and the concept of medical treatment,people can receive the fastest and most effective treatment for SAH that result in an enhancement long-term survivorship.Unfortunately,SAH survivors have to bear a huge mental and economic burden due to the long-term neurological complications,such as dementia and dyskinesia.Research shows that the cerebral vasospasm induced hypoxia is the main reason of these complications in the brain.When the cells become hypoxia,HIF will active and induce the expression of its target genes such as VEGF and EPO,so that prompt blood vessels to grow and increase blood flow in the brain,and finally,alleviate the SAH induced brain hypoxia.The retina,as a nearest neighbor of the brain,has a close functional and structural relation to the brain.Hypoxia caused by SAH is not confined to the brain only,the retina could also be implicated frequently.However,people only pay attention to the SAH caused fatal injury,they neglect the SAH induced visual dysfunction.In addition,SAH patients always have low level of consciousness and unable to cooperate with visual check.All of the above bring great difficulties to assess visual change.Therefore,there are no studies so far that identified specific pathogenesis of SAH caused visual dysfunction and no studies presented the methods of prevention and treatment.[Objective] To investigate the changes of retina structure and function in SAH rats.To investigate the effect of DFO on the SAH caused abnormal retina.And to explore the specific mechanisms of SAH caused visual dysfunction.To provide a target for prevention and treatment of SAH caused vision loss and an important theoretical basis for clinical research.[Methods and Results] In this experiment,experimental SAH of Sprague-Dawley(SD)rats was established by injection of 0.3 ml auto blood into the pre-chiasmatic cistern.Firstly,we investigated the changes of retinal structure and function after SAH.And we found that there was a mass of new blood vessel in the retina and grow into the vitreous cavity.And the new blood vessels became more obvious when hypoxia was aggravated.Then,to further understanding of the mechanisms of SAH induced visual dysfunction,we established experimental SAH of SD rats at 3 h,6 h,9h,12 h and on day 1,day 2,day 3,day 5,day7 and day 14 and we detected the time-courses expression pattern of HIF-1α,VEGF-A and activating transcription factor-4(ATF-4)in the brain and retina after SAH.We found that HIF-1α and VEGF-A increased gradually before the first day 1 and then declined from day 1 to day 5,after which there existed a significant increased from day 5 to day 14.ATF-4 could possibly be a positive regulator of HIF-1α.Finally,there was a marked increase in retinal NV after injected DFO intraperitoneally,and which owing to the impact of DFO on HIF-1α-ATF-4/VEGF-A expression.[Conclusion] We conclude that SAH induced ischemia and hypoxia in the brain and the retina of SD rats.The cells in the brain and the retina active HIF-1α-ATF-4/VEGF-A pathway to increase the ability of surviving in hypoxia condition.DFO can effectively relieves the retinal hypoxia after SAH by stabilize HIF-1α-ATF-4/VEG-A expression.