Platelet-Derived Growth Factor Subunit B Signaling Promotes Pericyte Migration in Response to Loud Sound in the Cochlear Stria Vascularis
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Normal blood supply to the cochlea is critical for hearing. Noise damages auditory sensory cells and has a marked effect on the microvasculature in the cochlear lateral wall. Pericytes in the stria vascularis (strial pericytes) are particularly vulnerable and sensitive to acoustic trauma. Exposure of NG2DsRedBAC transgenic mice (6–8 weeks old) to wide-band noise at a level of 120 dB for 3 h per day for 2 consecutive days produced a significant hearing threshold shift and caused pericytes to protrude and migrate from their normal endothelial attachment sites. The pericyte migration was associated with increased expression of platelet-derived growth factor beta (PDGF-BB). Blockade of PDGF-BB signaling with either imatinib, a potent PDGF-BB receptor (PDGFR) inhibitor, or APB5, a specific PDGFRβ blocker, significantly attenuated the pericyte migration from strial vessel walls. The PDGF-BB-mediated strial pericyte migration was further confirmed in an in vitro cell migration assay, as well as in an in vivo live animal model used in conjunction with confocal fluorescence microscopy. Pericyte migration took one of two different forms, here denoted protrusion and detachment. The protrusion is characterized by pericytes with a prominent triangular shape, or pericytes extending fine strands to neighboring capillaries. The detachment is characterized by pericyte detachment and movement away from vessels. We also found the sites of pericyte migration highly associated with regions of vascular leakage. In particular, under transmission electron microscopy (TEM), multiple vesicles at the sites of endothelial cells with loosely attached pericytes were observed. These data show that cochlear pericytes are markedly affected by acoustic trauma, causing them to display abnormal morphology. The effect of loud sound on pericytes is mediated by upregulation of PDGF-BB. Normal functioning pericytes are required for vascular stability.
Keywordsmouse cochlea loud sound pericyte stria vascularis
We would like to thank Drs. Neng Lingling and Wenjing Zhang (Oregon Hearing Research Center, Oregon Health and Science University) for their initial work in establishing a primary pericyte cell line from the stria vascularis in the Shi Lab. We also thank Dr. Alfred Nuttall (Oregon Hearing Research Center, Oregon Health and Science University) for his critical review and valuable discussion of the manuscript, Rachel Dumont Ph.D. for her assistance with the transmission electron microscopy, and Allan Kachelmeier B.S for his editing on this manuscript.
This research was supported by NIH/NIDCD R21 DC016157 (X.Shi), NIH/NIDCD R01 DC015781 (X.Shi), NIH/NIDCD R01-DC010844 (X.Shi), NIH P30-DC005983 (Peter Barr-Gillespie), Medical Research Foundation from Oregon Health and Science University MRF (X.Shi), and P01GM051487-20 (Manfred Auer).
Compliance with Ethical Standards
All authors have read and approved the manuscript.
All procedures in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at Oregon Health & Science University (IP 00000968).
Conflict of Interest
The authors declare that they have no conflict of interest.
- Chen YT, Chang FC, Wu CF, Chou YH, Hsu HL, Chiang WC, Shen J, Chen YM, Wu KD, Tsai TJ, Duffield JS, Lin SL (2011) Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int 80:1170–1181CrossRefGoogle Scholar
- Choudhury N, Chen F, Shi X, Nuttall AL, Wang RK (2009) Volumetric imaging of blood flow within cochlea in gerbil in vivo. IEEE J Sel Top Quantum Electron Pp:1–6Google Scholar
- Facchiano A, De Marchis F, Turchetti E, Facchiano F, Guglielmi M, Denaro A, Palumbo R, Scoccianti M, Capogrossi MC (2000) The chemotactic and mitogenic effects of platelet-derived growth factor-bb on rat aorta smooth muscle cells are inhibited by basic fibroblast growth factor. J Cell Sci 113(Pt 16):2855–2863Google Scholar
- Greenhalgh SN, Iredale JP, Henderson NC (2013) Origins of fibrosis: pericytes take centre stage. F1000prime Rep 5. https://doi.org/10.12703/P5-37
- Kim JM, Hong KS, Song WK, Bae D, Hwang IK, Kim JS, Chung HM (2016) Perivascular progenitor cells derived from human embryonic stem cells exhibit functional characteristics of pericytes and improve the retinal vasculature in a rodent model of diabetic retinopathy. Stem Cells Transl Med 5:1268–1276CrossRefGoogle Scholar
- Niu F, Yao H, Liao K, Buch S (2015) HIV Tat 101-mediated loss of pericytes at the blood-brain barrier involves PDGF-BB. Ther Targets Neurol Dis 2(1). https://doi.org/10.14800/ttnd.471
- Sano H, Sudo T, Yokode M, Murayama T, Kataoka H, Takakura N, Nishikawa S, Nishikawa S-I, Kita T (2001) Functional blockade of platelet-derived growth factor receptor-Β but not of receptor-Α prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E–deficient mice. Circulation 103:2955–2960CrossRefGoogle Scholar
- Sano H, Ueda Y, Takakura N, Takemura G, Doi T, Kataoka H, Murayama T, Xu Y, Sudo T, Nishikawa S (2002) Blockade of platelet-derived growth factor receptor-Β pathway induces apoptosis of vascular endothelial cells and disrupts glomerular capillary formation in neonatal mice. Am J Pathol 161:135–143CrossRefGoogle Scholar
- Wangemann P (2002) Cochlear blood flow regulation. Adv Otorhinolaryngol 59:51–57.Google Scholar
- Yamagishi S, Yonekura H, Yamamoto Y, Fujimori H, Sakurai S, Tanaka N, Yamamoto H (1999) Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab Investig 79:501–509Google Scholar