Fibrovascular coupling in the cochlea and pericyte recruitment after noise

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DESCRIPTION (provided by applicant): Cochlear microcirculation is essential for normal hearing, with reduction of cochlear blood flow and disruption of blood-labyrinth barrier (BLB) involved in a number of hearing disorders. Development of new treatments for vascular-related hearing loss requires a better understanding of control over cochlear blood flow (CBF) and repair of the BLB. In particular, we need to understand the local cellular control mechanisms at the level of the microcirculation, as well as the cellular repair mechanisms involved in vascular recovery. Our early findings suggest that pericytes play roles in controlling regional CBF through contractile activity and remodeling the vasculature after trauma-induced BLB damage. The signaling pathways, however, that control the contractile and adaptive activities of pericytes have not been identified. In the brain and retina, "neuro-vascular units" (NVUs), consisting of neurons, astrocytes, pericytes, and smooth muscle, provide direct and swift modulation of local blood flow to match metabolic demand. Cochlear fibrocytes, which resemble astrocytes and glial cells and play a role in recycling K+ from hair cells, are found to be morphologically connected to pericytes on the spiral ligament pre-capillaries. The findings suggest there may be a mechanism analogous to the NVU for regulation of blood flow in the cochlear microcirculation. This proposal, therefore, comprises four Aims to further investigate: 1) the role of fibrocyte-pericyte coupling in the regulation of pericytes and control of CBF; 2) the signaling mechanism of the fibrocyte-pericyte unit; 3) the functional role of fibrocyte-pericyte coupling in bridging between sound activity and CBF; and 4) pericyte recruitment in sound-produced BLB. This study, by providing fundamental knowledge on fibrocyte and pericyte function, will lay the foundation for better clinical management of inner ear disease, prevention of pericyte-related vascular damage, and development of effective clinical treatments for hearing loss. PUBLIC HEALTH RELEVANCE: A wide array of hearing disorders, including sudden sensorineural hearing loss, presbycusis, noise-induced hearing loss, tinnitus, auto-immune hearing loss, and vestibular disorders, involve dysfunction of the blood supply to the cochlea and disruption of the blood-labyrinth barrier (BLB) in the inner ear. It follows that development of new treatments for vascular disorder-related hearing loss will require a better understanding of cochlear blood flow and BLB physiology and pathology. The findings from this study will provide the basis for development of effective medical therapies for inner ear disease.