TRPV4 Regulates Endothelial Cell Metabolism and Disease via OPA1-Dependent Mitochondrial Dynamics

Endothelial cell (EC) metabolism plays a central role in vascular homeostasis, angiogenesis, and the pathogenesis of diseases such as tumor growth and cardiovascular dysfunction. Transient receptor potential vanilloid type 4 (TRPV4) is a mechanosensitive ion channel known to regulate key EC functions, including proliferation, migration, and angiogenesis; however, its role in endothelial metabolism remains unclear. In the present study, we investigated whether TRPV4 channels modulate endothelial function by regulating mitochondrial dynamics and metabolic activity. Confocal imaging revealed that normal endothelial cells (NEC) displayed perinuclear, rounded mitochondria, whereas TRPV4 knockout endothelial cells (KOEC) exhibited elongated, cytoplasm-dispersed mitochondria. Transmission electron microscopy confirmed these structural changes, showing well-defined cristae in KOEC. Flow cytometry demonstrated increased mitochondrial content in KOEC, accompanied by elevated expression of the mitochondrial biogenesis regulator PGC-1α. At the molecular level, KOEC demonstrated a higher fusion-to-fission protein ratio (OPA1/MFF), indicating enhanced mitochondrial fusion. Seahorse metabolic flux analysis further revealed increased basal and maximal oxygen consumption rates (OCR), ATP-linked respiration, and spare respiratory capacity in KOEC, all of which were attenuated by the OPA1 inhibitor MYLS22. Substrate utilization assays further revealed that TRPV4KOECs exhibited increased consumption of TCA cycle intermediates, as well as NADH and FADH substrates, compared to NECs and this effect was normalized by MYLS22. Functionally, MYLS22 treatment normalized abnormal EC proliferation, migration, and angiogenesis observed in KOEC. In vivo, MYLS22 restored normal tumor vascularization and suppressed tumor growth in endothelial-specific TRPV4 knockout mice. These findings reveal that TRPV4 channels regulate endothelial metabolism and angiogenesis through OPA1-dependent mitochondrial dynamics. Targeting TRPV4 or its downstream metabolic pathways may represent a promising therapeutic strategy for vascular and metabolic diseases characterized by endothelial dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.