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IP3R-TRPM4 Coupling Determines the Spatial Reach of Pericyte-Mediated Capillary Constriction
Vidya Murthy1, Alex Aupetit1, Ahmed Eltanahy1
1Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, 89557-0318, USA.
Biorxiv : the Preprint Server for Biology
|July 10, 2026
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.
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.
