Tumor microenvironment regulates endothelial cell transformation via modulation of TRPV4 channels

Abstract

Abnormal angiogenesis and hyper‐permeable vessels characterize the tumor vasculature. Together, these attributes contribute to atypical growth rate and metastasis of tumor cells. We have recently shown that the mechanosensitive ion channel, transient receptor vanilloid 4 (TRPV4) expression and activity is significantly reduced in tumor endothelial cells (TEC), and that activation of TRPV4 normalized tumor vasculature and improved cancer therapy. However, whether and how the tumor microenvironment downregulates TRPV4 and transforms normal endothelial cell phenotype remains unknown. To explore this, we repeatedly exposed normal human endothelial cells (NhEC) to human lung adenocarcinoma (tumor) cell conditioned media and measured phenotypic changes, angiogenesis, and functional expression of TRPV4. We found that treatment with cancer cell conditioned media changed NhEC to a tumor endothelial‐like phenotype (ThEC) as evidenced by; increased expression of tumor endothelial cell marker 8 (TEM8) and exhibition of abnormal angiogenesis on 2D‐Matrigels compared to normal NhEC. Mechanistically, we observed that expression and activity of TRPV4 was reduced in ThEC. Finally, we found that treatment with a Rho kinase inhibitor, Y‐27632 normalized abnormal tube formation exhibited by ThEC. Taken together, our results suggest that the tumor microenvironment transforms normal endothelial cells into tumor endothelial cell‐like phenotype through the downregulation of TRPV4.Support or Funding InformationNIH (1RO1HL119705), NIH (1R15CA202847‐01), and start‐up funds from NEOMED (CKT).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.