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      Fibro-Vascular Coupling in the Control of Cochlear Blood Flow

      1 , 1 , 2 , 3 , *
      PLoS ONE
      Public Library of Science

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          Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF) is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained.

          Methodology/Principal Findings

          We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter-connected fibrocytes to be positive for Na+/K+ ATPase β1 and S100. The connected fibrocytes display more Ca 2+ signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca 2+ sensor, fluo-4. Elevation of Ca 2+ in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca 2+ signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF). Cyclooxygenase-1 (COX-1) was required for capillary dilation.


          The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity.

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          Most cited references50

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          ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear.

          Extracellular ATP controls various signaling systems including propagation of intercellular Ca(2+) signals (ICS). Connexin hemichannels, P2x7 receptors (P2x7Rs), pannexin channels, anion channels, vesicles, and transporters are putative conduits for ATP release, but their involvement in ICS remains controversial. We investigated ICS in cochlear organotypic cultures, in which ATP acts as an IP(3)-generating agonist and evokes Ca(2+) responses that have been linked to noise-induced hearing loss and development of hair cell-afferent synapses. Focal delivery of ATP or photostimulation with caged IP(3) elicited Ca(2+) responses that spread radially to several orders of unstimulated cells. Furthermore, we recorded robust Ca(2+) signals from an ATP biosensor apposed to supporting cells outside the photostimulated area in WT cultures. ICS propagated normally in cultures lacking either P2x7R or pannexin-1 (Px1), as well as in WT cultures exposed to blockers of anion channels. By contrast, Ca(2+) responses failed to propagate in cultures with defective expression of connexin 26 (Cx26) or Cx30. A companion paper demonstrates that, if expression of either Cx26 or Cx30 is blocked, expression of the other is markedly down-regulated in the outer sulcus. Lanthanum, a connexin hemichannel blocker that does not affect gap junction (GJ) channels when applied extracellularly, limited the propagation of Ca(2+) responses to cells adjacent to the photostimulated area. Our results demonstrate that these connexins play a dual crucial role in inner ear Ca(2+) signaling: as hemichannels, they promote ATP release, sustaining long-range ICS propagation; as GJ channels, they allow diffusion of Ca(2+)-mobilizing second messengers across coupled cells.
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            Astrocytes and the regulation of cerebral blood flow.

            Moment-to-moment changes in local neuronal activity lead to dynamic changes in cerebral blood flow. Emerging evidence implicates astrocytes as one of the key players in coordinating this neurovascular coupling. Astrocytes are poised to sense glutamatergic synaptic activity over a large spatial domain via activation of metabotropic glutamate receptors and subsequent calcium signaling and via energy-dependent glutamate transport. Astrocyte foot processes can signal vascular smooth muscle by arachidonic acid pathways involving astrocytic cytochrome P450 epoxygenase, astrocytic cyclooxygenase-1 and smooth muscle cytochrome P450 omega-hydroxylase activities, and by astrocytic and smooth muscle potassium channels. Non-glutamatergic transmitters released from neurons, such as nitric oxide, cyclooxygenase-2 metabolites and vasoactive intestinal peptide, might modulate neurovascular signaling at the level of the astrocyte or smooth muscle. Thus, astrocytes have a pivotal role in dynamic signaling within the neurovascular unit. Important questions remain on how this signaling is integrated with other pathways in health and disease.
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              K+ cycling and the endocochlear potential.

              Sensory transduction in the cochlea and the vestibular labyrinth depends on the cycling of K+. In the cochlea, endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells into perilymph via basolateral K+ channels including KCNQ4. K+ may be taken up by fibrocytes in the spiral ligament and transported from cell to cell via gap junctions into strial intermediate cells. Gap junctions may include GJB2, GJB3 and GJB6. K+ is released from the intermediate cells into the intrastrial space via the KCNJ10 K+ channel that generates the endocochlear potential. From the intrastrial space, K+ is taken up across the basolateral membrane of strial marginal cells via the Na+/2Cl-/K+ cotransporter SLC12A2 and the Na+/K+-ATPase ATP1A1/ATP1B2. Strial marginal cells secrete K+ across the apical membrane into endolymph via the K+ channel KCNQ1/KCNE1, which concludes the cochlear cycle. A similar K+ cycle exists in the vestibular labyrinth. Endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells via basolateral K+ channels including KCNQ4. Fibrocytes connected by gap junctions including GJB2 may be involved in delivering K+ to vestibular dark cells. Extracellular K+ is taken up into vestibular dark cells via SLC12A2 and ATP1A1/ATP1B2 and released into endolymph via KCNQ1/KCNE1, which concludes the vestibular cycle. The importance of K+ cycling is underscored by the fact that mutations of KCNQ1, KCNE1, KCNQ4, GJB2, GJB3 and GJB6 lead to deafness in humans and that null mutations of KCNQ1, KCNE1, KCNJ10 and SLC12A2 lead to deafness in mouse models.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1 June 2011
                : 6
                : 6
                [1 ]Oregon Hearing Research Center, Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon, United States of America
                [2 ]The Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
                [3 ]Department of Otolaryngology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
                University of Arizona, United States of America
                Author notes

                Conceived and designed the experiments: XS. Performed the experiments: XS MD. Analyzed the data: XS MD. Wrote the paper: XS.

                Dai, Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 11
                Research Article
                Anatomy and Physiology
                Cardiovascular System
                Circulatory Physiology
                Neurological System
                Sensory Physiology
                Anatomy and Physiology
                Neurological System
                Sensory Physiology
                Sensory Systems
                Vascular Biology



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