Abstract
VEGF and VEGFR2 signaling is the major regulator of endothelial functions such as proliferation, migration, and angiogenesis. While many studies on the modulation of angiogenesis focus on targeting VEGF signaling, mechanical forces also play critical role. We have recently shown that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) negatively regulates angiogenesis via modulation of Rho/Rho kinase‐dependent endothelial mechanosensing. Nevertheless, it is not known if a cross‐talk exists between TRPV4 and VEGF signaling. To explore this nexus, we silenced TRPV4 in endothelial cells (EC) and measured VEGFR2 expression, localization, and phosphorylation. Immunofluorescence analysis revealed significant localization of total‐VEGFR2 around the perinuclear (Golgi) compartment in control EC. Small interfering RNA (siRNA) knockdown of TRPV4 significantly decreased perinuclear localization of VEGFR2. Interestingly, we found increased phosphorylation of VEGFR2 at Y1175 and its localization to the plasma membrane in TRPV4 knocked‐down cells. We also found increased plasma membrane localization of phospho‐VEGFR2 Y1175 in TRPV4 null EC. Western blot analysis further revealed a significant increase in phospho‐VEGFR2 at Y1175 in whole cell lysates and membrane fractions of TRPV4 knocked‐down cells compared to control siRNA‐treated cells. Finally, TRPV4 deletion/knockdown also increased VEGF‐mediated migration with localization of phospho‐VEGFR2 at the leading edge of migrating EC. Taken together, our results suggest that TRPV4 channels regulate VEGFR2 localization and activation to identify novel cross‐talk between mechanical (TRPV4) and soluble (VEGF) signaling in EC.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) R01HL119705 and National Cancer Institute (NCI) R15CA202847This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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