Na+/K+-ATPase α1 Identified as an Abundant Protein in the Blood-Labyrinth Barrier That Plays an Essential Role in the Barrier Integrity

Yang, Yue; Dai, Min; Wilson, Teresa; Omelchenko, Irina; Klimek, John; Wilmarth, Phillip A.; David, Larry L.; Nuttall, Alfred L.; Gillespie, Peter G.; Shi, Xiaorui

doi:10.1371/journal.pone.0016547

Cited by 62 publications

(70 citation statements)

References 51 publications

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“…The major tight junction-associated proteins in the strial capillaries are occludins, claudins, ZOs, and adherens-junction proteins (23,24). The present study found that tight-junction and adhesion proteins were down-regulated substantially in the absence of PVM/Ms.…”

Section: Discussionsupporting

confidence: 55%

“…In an earlier mass spectrometry study, strial capillaries were found rich in tight-junction and cell-adhesion proteins (24). The major tight junction-associated proteins in the strial capillaries are occludins, claudins, ZOs, and adherens-junction proteins (23,24).…”

Section: Discussionmentioning

confidence: 91%

“…The major tight junctionassociated proteins in the intrastrial fluid-blood barrier are occludin, claudins, zonula occludens, and adherens-junction proteins (22). Several tight-and adherens-junction proteins, including ZO-1, occludin, and vascular endothelial cadherin (vecadherin), have been found in the intrastrial fluid-blood barrier (23,24). In the in vitro models, mRNA levels for zo-1, occludin, and ve-cadherin, assessed with quantitative RT-PCR (qRT-PCR), were decreased dramatically in the absence of PVM/Ms (n = 3; P < 0.05) (Fig.…”

Section: Pvms Control Barrier Permeability By Affecting Global Expresmentioning

confidence: 99%

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Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid–blood barrier

Zhang

Dai

Fridberger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The microenvironment of the cochlea is maintained by the barrier between the systemic circulation and the fluids inside the stria vascularis. However, the mechanisms that control the permeability of the intrastrial fluid-blood barrier remain largely unknown. The barrier comprises endothelial cells connected to each other by tight junctions and an underlying basement membrane. In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of perivascular cells with both macrophage and melanocyte characteristics. The perivascular-resident macrophage-like melanocytes (PVM/Ms) are in close contact with vessels through cytoplasmic processes. Here we demonstrate that PVM/Ms have an important role in maintaining the integrity of the intrastrial fluid-blood barrier and hearing function. Using a cell culture-based in vitro model and a genetically induced PVM/M-depleted animal model, we show that absence of PVM/Ms increases the permeability of the intrastrial fluid-blood barrier to both lowand high-molecular-weight tracers. The increased permeability is caused by decreased expression of pigment epithelial-derived factor, which regulates expression of several tight junction-associated proteins instrumental to barrier integrity. When tested for endocochlear potential and auditory brainstem response, PVM/ M-depleted animals show substantial drop in endocochlear potential with accompanying hearing loss. Our results demonstrate a critical role for PVM/Ms in regulating the permeability of the intrastrial fluid-blood barrier for establishing a normal endocochlear potential hearing threshold. mouse cochlea | paracellular permeability | tight junction | capillary T he intrastrial fluid-blood barrier separates the stria vascularis (SV) from peripheral circulation. The integrity of the barrier is critical for maintaining inner ear homeostasis, especially for sustaining the endocochlear potential (EP), an essential driving force for hearing function (1-4). Disruption of the barrier is closely associated with a number of hearing disorders, including autoimmune inner ear disease, noise-induced hearing loss, agerelated hearing loss, and several genetically linked diseases (5-10). Despite the importance of the intrastrial fluid-blood barrier, little is understood about regulation of the barrier and the mechanisms that control its permeability.In the classic view, the intrastrial fluid-blood barrier comprises basement membrane and endothelial cells (ECs) that connect to each other with tight junctions (11) to form a diffusion barrier that prevents most blood-borne substances from entering the ear (2). In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of pericytes and perivascular-resident macrophage-like melanocytes (PVM/Ms) (12, 13). The PVM/Ms are not observed in other capillary regions such as in capillary beds of the spiral ligament. The PVM/Ms are in close contact with vessels through cytoplasmic processes. The structural complexity of PVM/Ms' capillar...

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 91%

Section: Pvms Control Barrier Permeability By Affecting Global Expresmentioning

confidence: 99%

See 1 more Smart Citation

Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid–blood barrier

Zhang

Dai

Fridberger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

201

272

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“…The systemic application of glucocorticoids causes side effects such as hyperglycemia and osteoporosis [Cope and Bova, 2008;Trune and Canlon, 2012]. Additionally, the efficacy of systemic glucocorticoid treatment of conditions affecting the inner ear is limited by the low blood flow to the cochlea and the blood-perilymph barrier, which result in low perilymph concentrations of the active compound [Nakashima et al, 2003;Yang et al, 2011]. To minimize side effects and achieve higher perilymph drug concentrations, administration of glucocorticoids directly to the round window membrane via intratympanic injection has been preclinically evaluated and translated into clinical practice [Bird et al, 2011;Chou et DOI: 10.1159/000487662 al., 2013; Han et al, 2015;Shea et al, 2012].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Sustained-Release Steroid Hydrogels in a Guinea Pig Model for Noise-Induced Hearing Loss

et al. 2018

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The otoprotective effects of thermoreversible poloxamer 407 hydrogels containing dexamethasone or triamcinolone acetonide were evaluated in an animal model of noise-induced hearing loss. Seven days after noise exposure, hearing threshold shifts at 16 kHz were significantly reduced in the 6% dexamethasone group (p < 0.05). Even though no significant differences in hair cell counts were found, histological analysis revealed a significantly higher spiral ganglion cell density in the first turn of the cochlea in this group (p < 0.05). No otoprotective effects were observed after the application of the triamcinolone acetonide hydrogels. As the findings of this study indicate potential otoprotective effects of sustained topical dexamethasone delivery in the setting of noise-induced hearing loss, this strategy merits further evaluation.

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“…The BLB within the perilymph-filled areas that are part of the blood-perilymph barrier include the cochlear spiral ligament, spiral limbus, modiolus, osseous spiral lamina, vestibular stromal vasculature and the sub-epithelial dark cell area 13 . The vestibular BLB unit in the rodent is similar to the rodent strial BLB unit at the light microscopic level: composed of vascular endothelial cells, pericytes and perivascular-resident macrophage-like melanocytes Recent studies have implicated loss of the integrity of the BLB in several inner ear pathologies including acoustic trauma, autoimmune inner ear disease, and presbycusis 3,7,8,[14][15][16] . Meniere's disease is a disabling syndrome of fluctuating hearing loss, episodic vertigo, and ear fullness, the etiology and pathophysiology of which remain poorly understood.…”

mentioning

confidence: 99%

Recent Research Trend for Ménièreʼs Disease

Nam¹

2017

Res Vestib Sci

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The ultrastructural organization of the blood labyrinthine barrier (BLB) was investigated in the human vestibular endorgan, the utricular macula, using postmortem specimens from individuals with documented normal auditory and vestibular function and surgical specimens from patients with intractable Meniere's disease. Transmission electron microscopic analysis of capillaries located in the normal human utricular stroma showed vascular endothelial cells with few pinocytotic vesicles, covered by a smooth and uniform basement membrane surrounded by pericyte processes. Meniere's disease specimens revealed differential ultrastructural pathological changes in the cellular elements of the microvasculature. With moderate degeneration of the BLB, there were numerous vesicles within the vascular endothelial cells (VECs), with increased numbers at the abluminal face, pericyte process detachment and disruption of the perivascular basement membrane surrounding the VECs. With severe degeneration of the BLB, there was severe vacuolization or frank apparent necrosis of VECs and loss of subcellular organelles. A higher severity of BLB degenerative changes was associated with a higher degree of basement membrane thickening and edematous changes within the vestibular stroma. This study presents the first ultrastructural analysis of the capillaries constituting the BLB in the human vestibular macula utricle from normal and Meniere's disease.In the inner ear, the term blood labyrinthine barrier (BLB) refers to the barrier between the vasculature and the inner ear fluids, either endolymph or perilymph 1, 2 . The BLB is critical for the maintenance of the inner ear fluid ionic homeostasis and for the prevention of the entry of deleterious substances into the inner ear 3 . By studying the penetration of dyes and drugs from the systemic circulation into the fluids of the inner ear, it can be shown that the BLB is selective and that the composition of the inner ear fluids is regulated and markedly different from that of blood or of other fluids such as cerebrospinal fluid 2 . Understanding the dynamics of the BLB is important to develop therapeutic drug delivery systems to the inner ear to block or enhance the BLB inflammatory response. The BLB in the cochlea is well studied in animal models 2,4,5 . Initial transmission electron microscopy (TEM) studies demonstrated that the BLB in the guinea pig stria vascularis and spiral ligament is composed of vascular endothelial cells (VECs) surrounded by a basement membrane 6 . More recent studies have noted that, in addition, the intrastrial BLB is composed of pericytes and perivascular-resident macrophage-like melanocytes [7][8][9][10][11] . The VECs line the interior surface of the blood vessels, connected by tight junctions, forming an interface between circulating blood and the rest of the vessel wall. Pericytes are the only cell type to intimately connect with VECs as they lie embedded within the endothelial basement membrane. The perivascular-resident macrophage-like melanocytes have foot pr...

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Na+/K+-ATPase α1 Identified as an Abundant Protein in the Blood-Labyrinth Barrier That Plays an Essential Role in the Barrier Integrity

Cited by 62 publications

References 51 publications

Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid–blood barrier

Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid–blood barrier

Evaluation of Sustained-Release Steroid Hydrogels in a Guinea Pig Model for Noise-Induced Hearing Loss

Recent Research Trend for Ménièreʼs Disease

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