TRPV4 promotes histamine receptor signaling in lymphatic endothelial cells

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Abstract Background The control of lymphatic permeability and flow is essential for homeostatic regulation of tissue fluid balance and immune responses. Histamine has been identified as an important signaling mediator involved in the regulation of lymphatic function. Histamine is released from activated perilymphatic mast cells and may also be produced by lymphatic endothelial cells (LECs) in response to flow-induced shear stress. The non-selective cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) is an important mediator of signaling by GPCRs, including histamine receptors. TRPV4 is activated in response to shear stress and is functionally expressed by LECs. We hypothesized that histamine receptors and TRPV4 interact in LECs, leading to activation of distinct downstream signaling pathways. This study examined the mechanistic link between TRPV4 activity and histaminergic signaling in LECs. Principle Results Histaminergic Ca 2+ signaling was examined in primary human LECs. Responses to histamine were mainly driven by the H1R histamine receptor, with some contribution by the H4R subtype, as determined using selective antagonists. H4R signaling in response to 4-methylhistamine was effectively prevented by either removal of extracellular Ca 2+ or block of TRPV4 activity, consistent with TRPV4-dependence. Conversely, activation of H4R resulted in marked sensitization of subsequent responses to the selective TRPV4 agonist GSK1016790A. This interaction was mediated through a PLA2-dependent mechanism. TRPV4 activity was required for histamine receptor-evoked translocation of the Ca 2+ -dependent transcription factor NFATc1 and for cytoskeletal remodeling. By contrast, the release of cytokines in response to activation of either histamine receptors or TRPV4 were largely independent processes. Conclusions This study identifies TRPV4 as an important mediator of histaminergic signaling in LECs. The findings provide further support for the involvement of TRPV4 in defining the nature and magnitude of endothelial signaling downstream of GPCRs. Highlights Histamine receptors are functionally expressed by primary human LECs TRPV4 is an important driver of H4R-evoked Ca 2+ signaling in LECs Histamine receptor activation sensitizes TRPV4 signaling in LECs TRPV4 promotes histamine-evoked NFATc1 translocation to the nucleus of LECs Histamine and TRPV4 evoked cytokine release from LECs involve distinct mechanisms Graphical abstract Graphical abstract. Histamine exerts its effects on lymphatic endothelial cells through interaction with the H1R and H4R receptor subtypes. H1R activation promotes Ca 2+ release from intracellular stores. Activation of the H4R leads to elevated intracellular Ca 2+ through crosstalk with the non-selective cation channel TRPV4. Interaction between H4R and TRPV4 is mediated through a PLA2-dependent mechanism. TRPV4 enhances histamine-evoked NFATc1 activation and translocation and cytoskeletal remodeling. In contrast, histamine receptor- and TRPV4-mediated cytokine release appear to involve mechanistically independent processes.

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