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TRPV4 channels regulate vascular integrity through stabilization of VE‐Cadherin junctions
Author(s) -
Cappelli Holly C,
Amin Vibhatsu,
Sharma Priya,
Kanugula Anantha K,
Adapala Ravi K,
Meszaros J. Gary,
Paruchuri Sailaja K,
Thodeti Charles K
Publication year - 2017
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.31.1_supplement.678.7
Subject(s) - matrigel , angiogenesis , trpv4 , microbiology and biotechnology , neovascularization , in vivo , immunostaining , mechanosensitive channels , chemistry , vascular endothelial growth factor , biology , pathology , cancer research , receptor , immunology , medicine , ion channel , immunohistochemistry , biochemistry , vegf receptors
Abnormal angiogenesis is a hallmark of pathological conditions characterized by leaky immature vessels. Most of the studies on pathological angiogenesis including vascular normalization strategies are focused on the inhibition of pro‐angiogenic growth factor signaling, which has been met with limited success. However, there are few studies on endogenous regulators and/or mechanical signaling in the regulation of pathological angiogenesis. We have recently found mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) to be functionally low in tumor‐derived endothelial cells which exhibit aberrant mechanosensitivity and abnormal angiogenesis that may be imparted due to high basal Rho activity. Further, we demonstrated that tumors grown in TRPV4KO animals show enhanced growth as well as leaky immature vasculature. In the present study, we investigated the molecular mechanisms by which TRPV4 modulates vascular integrity. First, immunostaining revealed that normal EC exhibited distinct VE‐cadherin expression at the cell‐cell contacts in vitro which is significantly reduced in TRPV4KO EC. Next, we measured vascular growth in varying stiffness Matrigel plugs (700–900 Pa) implanted in WT and TRPV4KO mice. Interestingly, we found increased vascular growth with increasing stiffness from TRPV4KO mice. In contrast, Matrigel plugs from WT mice showed no significant vascular growth with increasing stiffness. Surprisingly, we found a significant stiffness‐dependent reduction in VE‐cadherin positive vessels in Matrigel plugs from TRPV4KO mice compared to WT mice, despite an increase in vascular growth. Further, using an in vivo tumor model with WT and TRPV4KO mice, we found a significant increase in VE‐cadherin negative vessels in TRPV4KO mice compared to their WT counterparts. Functionally, we found tumor vessels are leaky which enhanced Lewis lung carcinoma (LLC) tumor metastasis to lung in TRPV4KO mice. Taken together, our findings suggest mechanosensitive ion channel TRPV4 regulates vessel integrity by maintaining VE‐cadherin expression at cell‐cell contacts and identifies TRPV4 as a novel target for vascular normalization therapies. Support or Funding Information This work is supported by American Heart Association (AHA) Grant‐in‐aid (14GRNT20380935), NIH‐R15CA202847, and start‐up funds from NEOMED (CKT).