VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss.

Jinhui Zhang,Qing Yu,Manfred Auer,Yunpei Zhang,Junha Song,Zhiqiang Hou,Xiaorui Shi,Han Jiang,Lingling Neng,Michael Hoa,George Burwood,Xiaohan Wang,Anders Fridberger

doi:10.1172/jci.insight.143285

Abstract

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.

Highlights

Adequate blood supply is fundamental for auditory function since the processes responsible for hearing in the inner ear demand large amounts of energy
Pericyte loss caused vascular damage and blood-barrier breakdown with a corresponding loss of sensory hair cells (HCs) and hearing sensitivity
Using advanced in vitro tissue explant models, we found the pericytes signaled by VEGFA165 were indispensable for new vascular sprouting

Summary

Introduction

Adequate blood supply is fundamental for auditory function since the processes responsible for hearing in the inner ear demand large amounts of energy. Maintenance of normal blood flow to the ear is critical for hearing. The most critical microvascular network in the cochlea is located in the cochlear stria vascularis. This vascular network receives the larger portion of cochlear blood flow [1]. It is essential for cochlear fluid ion homeostasis, for generating the endocochlear potential (EP) [2], on which mechanotransduction by hair cells (HCs) depends. The microvascular beds in this region constitute a tightly controlled blood-labyrinth barrier, with a rich population of pericytes, providing a timely supply of oxygen and nutrients to the cochlea [3]

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Conclusion