Oregon Health & Science
University, Portland, OR (United States). Dept. of Otolaryngology-Head & Neck Surgery. Oregon Hearing Research Center; OSTI
Oregon Health & Science University, Portland, OR (United States). Dept. of Otolaryngology-Head & Neck Surgery. Oregon Hearing Research Center
Oregon Health & Science University, Portland, OR (United States). Dept. of Otolaryngology-Head & Neck Surgery. Oregon Hearing Research Center; Harvard Medical School, Boston, MA (United States). Boston Children’s Hospital
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
Linköping Univ. (Sweden). Dept. of Biomedical and
Clinical Sciences
National Institutes of Health (NIH), Bethesda, MD (United States). National Inst. on Deafness and Other Communication Disorders (NIDCD). Auditory Development and Restoration Program
Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1–mediated (AAV1–mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.
@article{osti_1815938,
author = {Zhang, Jinhui and Hou, Zhiqiang and Wang, Xiaohan and Jiang, Han and Neng, Lingling and Zhang, Yunpei and Yu, Qing and Burwood, George and Song, Junha and Auer, Manfred and others},
title = {VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss},
annote = {Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1–mediated (AAV1–mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.},
doi = {10.1172/jci.insight.143285},
url = {https://www.osti.gov/biblio/1815938},
journal = {JCI Insight},
issn = {ISSN 2379-3708},
number = {8},
volume = {6},
place = {United States},
publisher = {American Society for Clinical Investigation},
year = {2021},
month = {03}}
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH); Medical Research Foundation