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3D Visualization of Retinal Vascular Pericytes in Mice by Immunostaining
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IP 3 R-TRPM4 Coupling Determines the Spatial Reach of Pericyte-Mediated Capillary Constriction.

Vidya Murthy, Alex Aupetit, Ahmed Eltanahy

    Biorxiv : the Preprint Server for Biology
    |July 10, 2026
    PubMed
    Summary

    Pericytes control blood flow by coordinating constriction across capillary branches. A novel IP3R-TRPM4 signaling pathway enables this coordinated response, allowing precise regulation of microvascular blood flow distribution.

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    Area of Science:

    • Physiology
    • Cell Biology
    • Microcirculation Research

    Background:

    • Pericytes ensheath capillaries, regulating microvascular diameter and blood flow distribution.
    • Pericyte projections at capillary bifurcations can influence multiple vessel segments simultaneously.
    • Understanding the mechanisms of pericyte-mediated blood flow control is crucial for microvascular research.

    Purpose of the Study:

    • To investigate the mechanisms by which pericytes coordinate contractile responses across multiple capillary branches.
    • To identify the molecular players involved in signal propagation between pericyte projections.
    • To elucidate the role of TRPM4 channels in regulating blood flow distribution in the microvasculature.

    Main Methods:

    • Optogenetic tools (acta2-opto-α1AR and acta2-CatCh mice) were used to activate Gq-coupled receptors and induce membrane depolarization.
    • Computational modeling was employed to understand the role of TRPM4 channels in signal coupling.
    • Calcium (Ca2+) imaging was performed to characterize signaling events.
    • Proximity ligation assays confirmed protein colocalization.
    • Pharmacological blockade and augmentation of TRPM4 channels were used to assess their function.

    Main Results:

    • Gq-coupled receptor activation caused localized constriction, while depolarization induced propagation to neighboring branches via gap junction-independent mechanisms.
    • Computational modeling and Ca2+ imaging identified TRPM4 channels as key mediators of signal propagation.
    • Two distinct Ca2+ events were observed: slow IP3R-mediated and fast VGCC-mediated transients.
    • Sustained IP3R-mediated signals activated TRPM4, enabling cross-projection constriction, while rapid VGCC transients led to TRPM4 inactivation.
    • TRPM4 and IP3 receptors were found to be in close proximity within pericytes.
    • IP3-induced constriction was dependent on TRPM4 activity and could be modulated by PKC.

    Conclusions:

    • An IP3R-TRPM4 signaling axis acts as a molecular switch controlling pericyte constriction.
    • This pathway gates whether constriction is branch-specific or coordinated across multiple capillary branches.
    • The findings enable precise, stimulus-dependent control of blood flow distribution in the microvasculature.