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TGF-β2/Smad3 Signaling Pathway Activation Through Enhancing VEGF and CD34 Ameliorates Cerebral Ischemia/Reperfusion Injury After Isoflurane Post-conditioning in Rats

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Abstract

Evidence has shown the therapeutic potential of isoflurane (ISO) in cerebral stroke. The present study investigated the mechanism of ISO on vascular endothelial growth factor (VEGF) and CD34 expression in a rat model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion for 24 h in rats. ISO was administered for 1.5 h when the reperfusion was initiated. Neurologic deficit scores, infarct volumes, HE staining, Nissl staining, and TUNEL staining were evaluated at 24 h after reperfusion. The levels of transforming growth factor (TGF)-β2, Smad3, p-Smad3, VEGF, and CD34 proteins were detected by immunofluorescence (IF) staining and Western blot assay. Administration of ISO significantly reduced the neurologic deficit scores, infarct volumes, and damaged and apoptotic cells after cerebral ischemia/reperfusion (I/R) injury (P < 0.05). Meanwhile, ISO post-conditioning significantly increased the expression levels of TGF-β2, p-Smad3, VEGF, and CD34 (P < 0.05), whereas the expression of Smad3 showed no difference (P > 0.05). However, Pirfenidone, a TGF-β2 inhibitor, decreased the expression levels of TGF-β2, p-Smad3, VEGF, and CD34 (P < 0.05). Moreover, the protective effects of ISO post-conditioning were negated by the inhibitor. The present study indicated that ISO attenuates brain damage by activating the TGF-β2/Smad3 signaling pathway and increasing the protein expression of VEGF and CD34 in the rat MCAO model.

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References

  1. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J (2011) Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123(4):e18–e209. https://doi.org/10.1161/CIR.0b013e3182009701

    Article  PubMed  Google Scholar 

  2. Wang W, Jiang B, Sun H, Ru X, Sun D, Wang L, Wang L, Jiang Y, Li Y, Wang Y, Chen Z, Wu S, Zhang Y, Wang D, Wang Y, Feigin VL (2017) Prevalence, incidence, and mortality of stroke in China: results from a nationwide population-based survey of 480 687 adults. Circulation 135(8):759–771. https://doi.org/10.1161/circulationaha.116.025250

    Article  PubMed  Google Scholar 

  3. Wechsler LR, Jovin TG (2012) Intravenous recombinant tissue-type plasminogen activator in the extended time window and the US Food and Drug Administration: confused about the time. Stroke 43(9):2517–2519. https://doi.org/10.1161/strokeaha.112.670554

    Article  PubMed  Google Scholar 

  4. Horbelt D, Denkis A, Knaus P (2012) A portrait of Transforming Growth Factor beta superfamily signalling: background matters. Int J Biochem Cell Biol 44(3):469–474. https://doi.org/10.1016/j.biocel.2011.12.013

    Article  CAS  PubMed  Google Scholar 

  5. Lyons RM, Moses HL (1990) Transforming growth factors and the regulation of cell proliferation. Eur J Biochem 187(3):467–473

    Article  CAS  PubMed  Google Scholar 

  6. Wang S, Yin J, Ge M, Dai Z, Li Y, Si J, Ma K, Li L, Yao S (2016) Transforming growth-beta 1 contributes to isoflurane postconditioning against cerebral ischemia-reperfusion injury by regulating the c-Jun N-terminal kinase signaling pathway. Biomed Pharmacother 78:280–290. https://doi.org/10.1016/j.biopha.2016.01.030

    Article  CAS  PubMed  Google Scholar 

  7. Adamczak J, Hoehn M (2015) Poststroke angiogenesis, con: dark side of angiogenesis. Stroke 46(5):e103–e104. https://doi.org/10.1161/strokeaha.114.007642

    Article  PubMed  Google Scholar 

  8. Goumans MJ, Liu Z, ten Dijke P (2009) TGF-beta signaling in vascular biology and dysfunction. Cell Res 19(1):116–127. https://doi.org/10.1038/cr.2008.326

    Article  CAS  PubMed  Google Scholar 

  9. ten Dijke P, Arthur HM (2007) Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol 8(11):857–869. https://doi.org/10.1038/nrm2262

    Article  CAS  PubMed  Google Scholar 

  10. Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156(3):965–976. https://doi.org/10.1016/s0002-9440(10)64964-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu J, Rossaint R, Sanders RD, Coburn M (2014) Toxic and protective effects of inhaled anaesthetics on the developing animal brain. Eur J Anaesthesiol 31(12):669–677. https://doi.org/10.1097/EJA.0000000000000073

    Article  CAS  PubMed  Google Scholar 

  12. Lavaur J, Le Nogue D, Lemaire M, Pype J, Farjot G, Hirsch EC, Michel PP (2017) The noble gas xenon provides protection and trophic stimulation to midbrain dopamine neurons. J Neurochem 142(1):14–28. https://doi.org/10.1111/jnc.14041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deng J, Lei C, Chen Y, Fang Z, Yang Q, Zhang H, Cai M, Shi L, Dong H, Xiong L (2014) Neuroprotective gases–fantasy or reality for clinical use? Prog Neurobiol 115:210–245. https://doi.org/10.1016/j.pneurobio.2014.01.001

    Article  CAS  PubMed  Google Scholar 

  14. Zhang B, Wei X, Cui X, Zhou H, Ding W, Li W (2008) Desflurane affords greater protection than halothane in the function of mitochondria against forebrain ischemia reperfusion injury in rats. Anesth Analg 106(4):1242–1249, table of contents. https://doi.org/10.1213/ane.0b013e318164f2a5

    Article  CAS  Google Scholar 

  15. Kim EJ, Kim SY, Lee JH, Kim JM, Kim JS, Byun JI, Koo BN (2015) Effect of isoflurane post-treatment on tPA-exaggerated brain injury in a rat ischemic stroke model. Korean J Anesthesiol 68(3):281–286. https://doi.org/10.4097/kjae.2015.68.3.281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao DA, Bi LY, Huang Q, Zhang FM, Han ZM (2016) Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis. Braz J Anesthesiol 66(6):613–621. https://doi.org/10.1016/j.bjane.2015.04.008

    Article  PubMed  Google Scholar 

  17. Cheon SY, Kim SY, Kam EH, Lee JH, Kim JM, Kim EJ, Kim TW, Koo BN (2017) Isoflurane preconditioning inhibits the effects of tissue-type plasminogen activator on brain endothelial cell in an in vitro model of ischemic stroke. Int J Med Sci 14(5):425–433. https://doi.org/10.7150/ijms.18037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Peng L, Yin J, Ge M, Wang S, Xie L, Li Y, Si JQ, Ma K (2019) Isoflurane post-conditioning ameliorates cerebral ischemia/reperfusion injury by enhancing angiogenesis through activating the Shh/Gli signaling pathway in rats. Front Neurosci 13:321. https://doi.org/10.3389/fnins.2019.00321

    Article  PubMed  PubMed Central  Google Scholar 

  19. Luo X, Zhao H, Hennah L, Ning J, Liu J, Tu H, Ma D (2015) Impact of isoflurane on malignant capability of ovarian cancer in vitro. Br J Anaesth 114(5):831–839. https://doi.org/10.1093/bja/aeu408

    Article  CAS  PubMed  Google Scholar 

  20. Yuan M, Ge M, Yin J, Dai Z, Xie L, Li Y, Liu X, Peng L, Zhang G, Si J, Ma K, Wang S (2018) Isoflurane post-conditioning down-regulates expression of aquaporin 4 in rats with cerebral ischemia/reperfusion injury and is possibly related to bone morphogenetic protein 4/Smad1/5/8 signaling pathway. Biomed Pharmacother 97:429–438. https://doi.org/10.1016/j.biopha.2017.10.082

    Article  CAS  PubMed  Google Scholar 

  21. Burghardt I, Tritschler F, Opitz CA, Frank B, Weller M, Wick W (2007) Pirfenidone inhibits TGF-beta expression in malignant glioma cells. Biochem Biophys Res Commun 354(2):542–547. https://doi.org/10.1016/j.bbrc.2007.01.012

    Article  CAS  PubMed  Google Scholar 

  22. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91

    Article  CAS  PubMed  Google Scholar 

  23. Gaidhani N, Sun F, Schreihofer D, Uteshev VV (2017) Duration of isoflurane-based surgical anesthesia determines severity of brain injury and neurological deficits after a transient focal ischemia in young adult rats. Brain Res Bull 134:168–176. https://doi.org/10.1016/j.brainresbull.2017.07.018

    Article  CAS  PubMed  Google Scholar 

  24. Zhang YJ, Wu MJ, Yu H, Liu J (2017) Emulsified isoflurane postconditioning improves survival and neurological outcomes in a rat model of cardiac arrest. Exp Ther Med 14(1):65–72. https://doi.org/10.3892/etm.2017.4446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lu J, Wu Y, Sousa N, Almeida OF (2005) SMAD pathway mediation of BDNF and TGF beta 2 regulation of proliferation and differentiation of hippocampal granule neurons. Development 132(14):3231–3242. https://doi.org/10.1242/dev.01893

    Article  CAS  PubMed  Google Scholar 

  26. Polazzi E, Altamira LE, Eleuteri S, Barbaro R, Casadio C, Contestabile A, Monti B (2009) Neuroprotection of microglial conditioned medium on 6-hydroxydopamine-induced neuronal death: role of transforming growth factor beta-2. J Neurochem 110(2):545–556. https://doi.org/10.1111/j.1471-4159.2009.06117.x

    Article  CAS  PubMed  Google Scholar 

  27. Dhandapani KM, Wade FM, Mahesh VB, Brann DW (2005) Astrocyte-derived transforming growth factor-{beta} mediates the neuroprotective effects of 17{beta}-estradiol: involvement of nonclassical genomic signaling pathways. Endocrinology 146(6):2749–2759. https://doi.org/10.1210/en.2005-0014

    Article  CAS  PubMed  Google Scholar 

  28. Hu Z, Fan J, Zeng L, Lu W, Tang X, Zhang J, Li T (2008) Transient cerebral ischemia leads to TGF-beta2 expression in Golgi apparatus organelles. Curr Neurovasc Res 5(3):178–184

    Article  CAS  PubMed  Google Scholar 

  29. Huang Q, Zhong W, Hu Z, Tang X (2018) A review of the role of cav-1 in neuropathology and neural recovery after ischemic stroke. J Neuroinflammation 15(1):348. https://doi.org/10.1186/s12974-018-1387-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A (2014) Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells 32(6):1380–1389. https://doi.org/10.1002/stem.1661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao Y, Pang Q, Liu M, Pan J, Xiang B, Huang T, Tu F, Liu C, Chen X (2017) Treadmill exercise promotes neurogenesis in ischemic rat brains via caveolin-1/VEGF signaling pathways. Neurochem Res 42(2):389–397. https://doi.org/10.1007/s11064-016-2081-z

    Article  CAS  PubMed  Google Scholar 

  32. Liu Y, Li Y, Zhan M, Liu Y, Li Z, Li J, Cheng G, Teng G, Lu L (2018) Astrocytic cytochrome P450 4A/20-hydroxyeicosatetraenoic acid contributes to angiogenesis in the experimental ischemic stroke. Brain Res. https://doi.org/10.1016/j.brainres.2018.12.023

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zheng XW, Shan CS, Xu QQ, Wang Y, Shi YH, Wang Y, Zheng GQ (2018) Buyang Huanwu decoction targets SIRT1/VEGF pathway to promote angiogenesis after cerebral ischemia/reperfusion injury. Front Neurosci 12:911. https://doi.org/10.3389/fnins.2018.00911

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zhang J, Yao C, Chen J, Zhang Y, Yuan S, Lin Y (2016) Hyperforin promotes post-stroke functional recovery through interleukin (IL)-17A-mediated angiogenesis. Brain Res 1646:504–513. https://doi.org/10.1016/j.brainres.2016.06.025

    Article  CAS  PubMed  Google Scholar 

  35. Chaitanya GV, Minagar A, Alexander JS (2014) Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia. Cell Commun Signal (CCS) 12:7. https://doi.org/10.1186/1478-811x-12-7

    Article  Google Scholar 

  36. Dirnagl U (2012) Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann N Y Acad Sci 1268:21–25. https://doi.org/10.1111/j.1749-6632.2012.06691.x

    Article  PubMed  Google Scholar 

  37. Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, Cao X (2018) Transforming growth factor-beta in stem cells and tissue homeostasis. Bone Res 6:2. https://doi.org/10.1038/s41413-017-0005-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Loeys BL, Mortier G, Dietz HC (2013) Bone lessons from Marfan syndrome and related disorders: fibrillin, TGF-B and BMP at the balance of too long and too short. Pediatr Endocrinol Rev (PER) 10(Suppl 2):417–423

    Google Scholar 

  39. Futakuchi A, Inoue T, Fujimoto T, Kuroda U, Inoue-Mochita M, Takahashi E, Ohira S, Tanihara H (2017) Molecular mechanisms underlying the filtration bleb-maintaining effects of suberoylanilide hydroxamic acid (SAHA). Invest Ophthalmol Vis Sci 58(4):2421–2429. https://doi.org/10.1167/iovs.16-21403

    Article  CAS  PubMed  Google Scholar 

  40. Jeong HS, Yun JH, Lee DH, Lee EH, Cho CH (2019) Retinal pigment epithelium-derived transforming growth factor-beta2 inhibits the angiogenic response of endothelial cells by decreasing vascular endothelial growth factor receptor-2 expression. J Cell Physiol 234(4):3837–3849. https://doi.org/10.1002/jcp.27156

    Article  CAS  PubMed  Google Scholar 

  41. Maring JA, van Meeteren LA, Goumans MJ, Ten Dijke P (2016) Interrogating TGF-beta function and regulation in endothelial cells. Methods Mol Biol 1344:193–203. https://doi.org/10.1007/978-1-4939-2966-5_11

    Article  CAS  PubMed  Google Scholar 

  42. Colak S, Ten Dijke P (2017) Targeting TGF-beta signaling in cancer. Trends Cancer 3(1):56–71. https://doi.org/10.1016/j.trecan.2016.11.008

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was performed at the Key Laboratory of Xinjiang Endemic and Ethnic Diseases of Xinjiang Provincial Department of Physiology, School of Medicine, Shihezi University. This work was supported by the National Natural Science Foundation of China (Grant Number: 81860249, 81360203).

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Author notes

  1. Li Peng and Jiangwen Yin contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17 Lujiang Road, Hefei, 230001, Anhui Province, People’s Republic of China

    Sheng Wang

  2. Department of Anesthesiology, First Affiliated Hospital of Henan University, Hennan University, Kaifeng, 475000, China

    Li Peng

  3. Department of Anesthesiology, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832002, China

    Jiangwen Yin, Mingyue Ge, Meng Zhang, Liping Xie & Yan Li

  4. Department of Physiology, School of Medicine, Shihezi University and the Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University, Shihezi, 832002, China

    Ziwei Han

  5. Department of Ultrasound, Xinyang Central Hospital, Henan, xinyang, 464000, China

    Yan Wang

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  1. Li Peng
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Peng, L., Yin, J., Wang, S. et al. TGF-β2/Smad3 Signaling Pathway Activation Through Enhancing VEGF and CD34 Ameliorates Cerebral Ischemia/Reperfusion Injury After Isoflurane Post-conditioning in Rats. Neurochem Res 44, 2606–2618 (2019). https://doi.org/10.1007/s11064-019-02880-8

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