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TRPV4 Channels Modulate Pathological Angiogenesis via Rho/Rho Kinase Pathway
Author(s) -
Cappelli Holly,
Thoppil Roslin,
Adapala Ravi,
Paruchuri Sailaja,
Meszaros J.,
Thodeti Charles
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.844.21
Subject(s) - trpv4 , angiogenesis , mechanosensitive channels , pericyte , transient receptor potential channel , cancer research , chemistry , microbiology and biotechnology , rho associated protein kinase , tec , endocrinology , medicine , kinase , biology , endothelial stem cell , receptor , ion channel , in vitro , biochemistry , ionosphere , physics , astronomy
Solid tumors require angiogenesis for continuous supply of oxygen and nutrients to grow and metastasize, however the endless needs of the tumor create blood vessels that are structurally and functionally abnormal. We have recently found mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) to be functionally low in tumor‐derived endothelial cells (TEC), which exhibit aberrant mechanosensitivity and abnormal angiogenesis that may be imparted due to high basal Rho activity. In the current study, we investigated if TRPV4 modulates pathological or abnormal angiogenesis via regulation of the Rho/Rho Kinase pathway. While basal Rho activity is high in TEC, overexpression or pharmacological activation of TRPV4 reduced Rho activity to that comparable to normal endothelial cells (NEC). Importantly, activation of TRPV4 and/or inhibition of Rho decreased the abnormally high rate of migration found among TEC. Further, we found that Rho Kinase inhibitor, Y‐27632, normalized abnormal tube formation displayed by TEC and TRPV4 null (TRPV4KO) endothelial cells. Furthermore, using an in vivo tumor model with wild type (WT) and TRPV4KO mice, we found a significant increase in tumor volume and abnormal vessels (poor pericyte coverage) in KO mice compared to their WT counterparts. Finally, we found that Y‐27632 treatment restored pericyte coverage, and in combination with a chemotherapeutic drug, Cisplatin, reduced tumor growth. Altogether our findings suggest mechanosensitive ion channel TRPV4 regulates pathological angiogenesis via modulation of the Rho/Rho Kinase pathway and provide a novel approach to normalize tumor vasculature and improve chemotherapy.