Activation of Src Kinase Mediates the Disruption of Adherens Junction in the Blood-labyrinth Barrier after Acoustic Trauma


Cite item

Full Text

Abstract

Background:Adherens junction in the blood-labyrinth barrier is largely unexplored because it is traditionally thought to be less important than the tight junction. Since increasing evidence indicates that it actually functions upstream of tight junction adherens junction may potentially be a better target for ameliorating the leakage of the blood-labyrinth barrier under pathological conditions such as acoustic trauma.

Aims:This study was conducted to investigate the pathogenesis of the disruption of adherens junction after acoustic trauma and explore potential therapeutic targets.

Methods:Critical targets that regulated the disruption of adherens junction were investigated by techniques such as immunofluorescence and Western blotting in C57BL/6J mice.

Results:Upregulation of Vascular Endothelial Growth Factor (VEGF) and downregulation of Pigment Epithelium-derived Factor (PEDF) coactivated VEGF-PEDF/VEGF receptor 2 (VEGFR2) signaling pathway in the stria vascularis after noise exposure. Downstream effector Src kinase was then activated to degrade VE-cadherin and dissociate adherens junction, which led to the leakage of the blood-labyrinth barrier. By inhibiting VEGFR2 or Src kinase, VE-cadherin degradation and blood-labyrinth barrier leakage could be attenuated, but Src kinase represented a better target to ameliorate blood-labyrinth barrier leakage as inhibiting it would not interfere with vascular endothelium repair, neurotrophy and pericytes proliferation mediated by upstream VEGFR2.

Conclusion:Src kinase may represent a promising target to relieve noise-induced disruption of adherens junction and hyperpermeability of the blood-labyrinth barrier.

About the authors

Jianbin Sun

, Medical School of Chinese PLA

Email: info@benthamscience.net

Tong Zhang

, Medical School of Chinese PLA

Email: info@benthamscience.net

Chaoying Tang

Department of Otorhinolaryngology Head and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University

Email: info@benthamscience.net

Shuhang Fan

, Medical School of Chinese PLA

Email: info@benthamscience.net

Qin Wang

, Medical School of Chinese PLA

Email: info@benthamscience.net

Da Liu

, Medical School of Chinese PLA

Email: info@benthamscience.net

Na Sai

, Medical School of Chinese PLA

Email: info@benthamscience.net

Qi Ji

, Liaoning Women and Children's Hospital

Email: info@benthamscience.net

Weiwei Guo

, Medical School of Chinese PLA

Author for correspondence.
Email: info@benthamscience.net

Weiju Han

, Medical School of Chinese PLA

Author for correspondence.
Email: info@benthamscience.net

References

  1. Hibino H, Nin F, Tsuzuki C, Kurachi Y. How is the highly positive endocochlear potential formed? The specific architecture of the stria vascularis and the roles of the ion-transport apparatus. Pflugers Arch 2010; 459(4): 521-33. doi: 10.1007/s00424-009-0754-z PMID: 20012478
  2. Cosentino A, Agafonova A, Modafferi S, et al. Blood–labyrinth barrier in health and diseases: Effect of hormetic nutrients. Antioxid Redox Signal 2024; 40(7-9): 542-63. doi: 10.1089/ars.2023.0251 PMID: 37565276
  3. Ke Y, Ma X, Jing Y, Diao T, Yu L. The breakdown of blood-labyrinth barrier makes it easier for drugs to enter the inner ear. Laryngoscope 2024; 134(5): 2377-86. doi: 10.1002/lary.31194 PMID: 37987231
  4. Shi X. Pathophysiology of the cochlear intrastrial fluid-blood barrier (review). Hear Res 2016; 338: 52-63. doi: 10.1016/j.heares.2016.01.010 PMID: 26802581
  5. Ohlemiller KK, Dwyer N, Henson V, Fasman K, Hirose K. A critical evaluation of "leakage" at the cochlear blood-stria-barrier and its functional significance. Front Mol Neurosci 2024; 17: 1368058. doi: 10.3389/fnmol.2024.1368058 PMID: 38486963
  6. Wu J, Han W, Chen X, et al. Matrix metalloproteinase-2 and −9 contribute to functional integrity and noise-induced damage to the blood-labyrinth-barrier. Mol Med Rep 2017; 16(2): 1731-8. doi: 10.3892/mmr.2017.6784 PMID: 28627704
  7. Wu YX, Zhu GX, Liu XQ, et al. Noise alters guinea pig’s blood-labyrinth barrier ultrastructure and permeability along with a decrease of cochlear Claudin-5 and Occludin. BMC Neurosci 2014; 15(1): 136. doi: 10.1186/s12868-014-0136-0 PMID: 25539640
  8. Bahloul A, Simmler MC, Michel V, et al. Vezatin, an integral membrane protein of adherens junctions, is required for the sound resilience of cochlear hair cells. EMBO Mol Med 2009; 1(2): 125-38. doi: 10.1002/emmm.200900015 PMID: 20049712
  9. Sai N, Zhang T, Wu J, Han WJ. Noise-induced blood-labyrinth-barrier trauma of guinea pig and the protective effect of matrix metalloproteinase inhibitors. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020; 55(4): 363-70. PMID: 32306634
  10. Liu X, Zheng G, Wu Y, et al. Lead exposure results in hearing loss and disruption of the cochlear blood–labyrinth barrier and the protective role of iron supplement. Neurotoxicology 2013; 39: 173-81. doi: 10.1016/j.neuro.2013.10.002 PMID: 24144481
  11. Gu J, Tong L, Lin X, et al. The disruption and hyperpermeability of blood-labyrinth barrier mediates cisplatin-induced ototoxicity. Toxicol Lett 2022; 354: 56-64. doi: 10.1016/j.toxlet.2021.10.015 PMID: 34757176
  12. Garcia MA, Nelson WJ, Chavez N. Cell–cell junctions organize structural and signaling networks. Cold Spring Harb Perspect Biol 2018; 10(4): a029181. doi: 10.1101/cshperspect.a029181 PMID: 28600395
  13. Tietz S, Engelhardt B. Brain barriers: Crosstalk between complex tight junctions and adherens junctions. J Cell Biol 2015; 209(4): 493-506. doi: 10.1083/jcb.201412147 PMID: 26008742
  14. Campbell HK, Maiers JL, DeMali KA. Interplay between tight junctions & adherens junctions. Exp Cell Res 2017; 358(1): 39-44. doi: 10.1016/j.yexcr.2017.03.061 PMID: 28372972
  15. Li W, Chen Z, Chin I, Chen Z, Dai H. The role of VE-cadherin in blood-brain barrier integrity under central nervous system pathological conditions. Curr Neuropharmacol 2018; 16(9): 1375-84. doi: 10.2174/1570159X16666180222164809 PMID: 29473514
  16. Ninchoji T, Love DT, Smith RO, et al. eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin. eLife 2021; 10: e64944. doi: 10.7554/eLife.64944 PMID: 33908348
  17. Shen D, Ye X, Li J, et al. Metformin preserves VE–Cadherin in choroid plexus and attenuates hydrocephalus via VEGF/VEGFR2/p-Src in an intraventricular hemorrhage rat model. Int J Mol Sci 2022; 23(15): 8552. doi: 10.3390/ijms23158552 PMID: 35955686
  18. Bielefeld EC. Protection from noise-induced hearing loss with Src inhibitors. Drug Discov Today 2015; 20(6): 760-5. doi: 10.1016/j.drudis.2015.01.010 PMID: 25637168
  19. Bielefeld EC, Hangauer D, Henderson D. Protection from impulse noise-induced hearing loss with novel Src-protein tyrosine kinase inhibitors. Neurosci Res 2011; 71(4): 348-54. doi: 10.1016/j.neures.2011.07.1836 PMID: 21840347
  20. Bielefeld EC, Tanaka C, Chen G, et al. An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect. Anticancer Drugs 2013; 24(1): 43-51. doi: 10.1097/CAD.0b013e32835739fd PMID: 22828384
  21. Harris KC, Hu B, Hangauer D, Henderson D. Prevention of noise-induced hearing loss with Src-PTK inhibitors. Hear Res 2005; 208(1-2): 14-25. doi: 10.1016/j.heares.2005.04.009 PMID: 15950415
  22. Fetoni AR, Bielefeld EC, Paludetti G, Nicotera T, Henderson D. A putative role of p53 pathway against impulse noise induced damage as demonstrated by protection with pifithrin-alpha and a Src inhibitor. Neurosci Res 2014; 81-82: 30-7. doi: 10.1016/j.neures.2014.01.006 PMID: 24472721
  23. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell 2019; 176(6): 1248-64. doi: 10.1016/j.cell.2019.01.021 PMID: 30849371
  24. Zhou W, Liu K, Zeng L, et al. Targeting VEGF-A/VEGFR2 Y949 signaling-mediated vascular permeability alleviates hypoxic pulmonary hypertension. Circulation 2022; 146(24): 1855-81. doi: 10.1161/CIRCULATIONAHA.122.061900 PMID: 36384284
  25. Zhang SX, Wang JJ, Gao G, Parke K, Ma J. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy. J Mol Endocrinol 2006; 37(1): 1-12. doi: 10.1677/jme.1.02008 PMID: 16901919
  26. Zhang M, Tombran-Tink J, Yang S, Zhang X, Li X, Barnstable CJ. PEDF is an endogenous inhibitor of VEGF-R2 angiogenesis signaling in endothelial cells. Exp Eye Res 2021; 213: 108828. doi: 10.1016/j.exer.2021.108828 PMID: 34742690
  27. Picciotti PM, Fetoni AR, Paludetti G, et al. Vascular endothelial growth factor (VEGF) expression in noise-induced hearing loss. Hear Res 2006; 214(1-2): 76-83. doi: 10.1016/j.heares.2006.02.004 PMID: 16603326
  28. Zhang F, Dai M, Neng L, et al. Perivascular macrophage-like melanocyte responsiveness to acoustic trauma-a salient feature of strial barrier associated hearing loss. FASEB J 2013; 27(9): 3730-40. doi: 10.1096/fj.13-232892 PMID: 23729595
  29. Yan Y, Ma L, Zhou X, et al. Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int 2016; 89(1): 68-81. doi: 10.1038/ki.2015.293 PMID: 26444028
  30. Huang TH, Sun CK, Chen YL, et al. Shock wave therapy enhances angiogenesis through VEGFR2 activation and recycling. Mol Med 2016; 22(1): 850-62. doi: 10.2119/molmed.2016.00108 PMID: 27925633
  31. Chetty S, Engquist EN, Mehanna E, Lui KO, Tsankov AM, Melton DA. A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation. J Cell Biol 2015; 210(7): 1257-68. doi: 10.1083/jcb.201502035 PMID: 26416968
  32. Rutledge CA, Ng FS, Sulkin MS, et al. c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. J Am Coll Cardiol 2014; 63(9): 928-34. doi: 10.1016/j.jacc.2013.10.081 PMID: 24361364
  33. Lipovsek M, Elgoyhen AB. The evolutionary tuning of hearing. Trends Neurosci 2023; 46(2): 110-23. doi: 10.1016/j.tins.2022.12.002 PMID: 36621369
  34. Juhn SK, Rybak LP. Labyrinthine barriers and cochlear homeostasis. Acta Otolaryngol 1981; 91(1-6): 529-34. doi: 10.3109/00016488109138538 PMID: 6791457
  35. Schmutzhard J, Kositz CH, Glueckert R, Schmutzhard E, Schrott-Fischer A, Lackner P. Apoptosis of the fibrocytes type 1 in the spiral ligament and blood labyrinth barrier disturbance cause hearing impairment in murine cerebral malaria. Malar J 2012; 11(1): 30. doi: 10.1186/1475-2875-11-30 PMID: 22297132
  36. Neng L, Zhang J, Yang J, et al. Structural changes in thestrial blood–labyrinth barrier of aged C57BL/6 mice. Cell Tissue Res 2015; 361(3): 685-96. doi: 10.1007/s00441-015-2147-2 PMID: 25740201
  37. Zhang J, Chen S, Cai J, et al. Culture media-based selection of endothelial cells, pericytes, and perivascular-resident macrophage like melanocytes from the young mouse vestibular system. Hear Res 2017; 345: 10-22. doi: 10.1016/j.heares.2016.12.012 PMID: 28087417
  38. Shi X. Research advances in cochlear pericytes and hearing loss. Hear Res 2023; 438: 108877. doi: 10.1016/j.heares.2023.108877 PMID: 37651921
  39. Morini MF, Giampietro C, Corada M, et al. VE-cadherin–mediated epigenetic regulation of endothelial gene expression. Circ Res 2018; 122(2): 231-45. doi: 10.1161/CIRCRESAHA.117.312392 PMID: 29233846
  40. Sekulic M, Puche R, Bodmer D, Petkovic V. Human blood-labyrinth barrier model to study the effects of cytokines and inflammation. Front Mol Neurosci 2023; 16: 1243370. doi: 10.3389/fnmol.2023.1243370 PMID: 37808472
  41. Dejana E, Tournier-Lasserve E, Weinstein BM. The control of vascular integrity by endothelial cell junctions: Molecular basis and pathological implications. Dev Cell 2009; 16(2): 209-21. doi: 10.1016/j.devcel.2009.01.004 PMID: 19217423
  42. Vestweber D, Winderlich M, Cagna G, Nottebaum AF. Cell adhesion dynamics at endothelial junctions: VE-cadherin as a major player. Trends Cell Biol 2009; 19(1): 8-15. doi: 10.1016/j.tcb.2008.10.001 PMID: 19010680
  43. Cai J, Wu L, Qi X, et al. PEDF regulates vascular permeability by a γ-secretase-mediated pathway. PLoS One 2011; 6(6): e21164. doi: 10.1371/journal.pone.0021164 PMID: 21695048
  44. Kaur C, Ling E. Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res 2008; 5(1): 71-81. doi: 10.2174/156720208783565645 PMID: 18289024
  45. Shi X, Doycheva DM, Xu L, Tang J, Yan M, Zhang JH. Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats. Neurobiol Dis 2016; 95: 111-21. doi: 10.1016/j.nbd.2016.07.016 PMID: 27425892
  46. Yang D, Zhou H, Zhang J, Liu L. Increased endothelial progenitor cell circulation and VEGF production in a rat model of noise-induced hearing loss. Acta Otolaryngol 2015; 135(6): 622-8. doi: 10.3109/00016489.2014.1003092 PMID: 25720428
  47. Yamashita T, Abe K. Mechanisms of endogenous endothelial repair in stroke. Curr Pharm Des 2012; 18(25): 3649-52. doi: 10.2174/138161212802002832 PMID: 22574978
  48. Monge Naldi A, Gassmann M, Bodmer D. Erythropoietin but not VEGF has a protective effect on auditory hair cells in the inner ear. Cell Mol Life Sci 2009; 66(22): 3595-9. doi: 10.1007/s00018-009-0144-x PMID: 19763398
  49. Zhang J, Hou Z, Wang X, et al. VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss. JCI Insight 2021; 6(8): e143285. doi: 10.1172/jci.insight.143285 PMID: 33690221
  50. Ueda S, Yamagishi SI, Okuda S. Anti-vasopermeability effects of PEDF in retinal-renal disorders. Curr Mol Med 2010; 10(3): 279-83. doi: 10.2174/156652410791065291 PMID: 20236056
  51. Hui HL, Jiang B, Zhou YY, et al. PEDF inhibits VEGF-induced vascular leakage through binding to VEGFR2 in acute myocardial infarction. J Biomol Struct Dyn 2024; 12(2): 1-13. doi: 10.1080/07391102.2024.2314260 PMID: 38345053
  52. Zhang J, Fan W, Neng L, Chen B, Zuo B, Lu W. Long non-coding RNA Rian promotes the expression of tight junction proteins in endothelial cells by regulating perivascular-resident macrophage like melanocytes and PEDF secretion. Hum Cell 2021; 34(4): 1093-102. doi: 10.1007/s13577-021-00521-3 PMID: 33768511
  53. Yu Q, Liu S, Guo R, et al. Complete restoration of hearing loss and cochlear synaptopathy via minimally invasive, single-dose, and controllable middle ear delivery of brain-derived neurotrophic Factor–Poly( DL -lactic acid- co -glycolic acid)-loaded Hydrogel. ACS Nano 2024; 18(8): 6298-313. doi: 10.1021/acsnano.3c11049 PMID: 38345574
  54. Ingersoll MA, Lutze RD, Kelmann RG, et al. KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss. J Neurosci 2024; 44(18): e2174232024. doi: 10.1523/JNEUROSCI.2174-23.2024 PMID: 38548338
  55. Tan WJT, Song L. Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss. Hear Res 2023; 434: 108783. doi: 10.1016/j.heares.2023.108783 PMID: 37167889
  56. Feng B, Dong T, Song X, et al. Personalized porous gelatin methacryloyl sustained-release nicotinamide protects against noise-induced hearing loss. Adv Sci (Weinh) 2024; 11(12): 2305682. doi: 10.1002/advs.202305682 PMID: 38225752
  57. Chen MB, Li MH, Wu LY, et al. Oridonin employs interleukin 1 receptor type 2 to treat noise-induced hearing loss by blocking inner ear inflammation. Biochem Pharmacol 2023; 210: 115457. doi: 10.1016/j.bcp.2023.115457 PMID: 36806583
  58. Lye J, Delaney DS, Leith FK, et al. Recent therapeutic progress and future perspectives for the treatment of hearing loss. Biomedicines 2023; 11(12): 3347. doi: 10.3390/biomedicines11123347 PMID: 38137568
  59. Saidia AR, François F, Casas F, et al. Oxidative stress plays an important role in glutamatergic excitotoxicity-induced cochlear synaptopathy: Implication for therapeutic molecules screening. Antioxidants 2024; 13(2): 149. doi: 10.3390/antiox13020149 PMID: 38397748
  60. Xu K, Xu B, Gu J, Wang X, Yu D, Chen Y. Intrinsic mechanism and pharmacologic treatments of noise-induced hearing loss. Theranostics 2023; 13(11): 3524-49. doi: 10.7150/thno.83383 PMID: 37441605

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers