Abstract
Angiogenesis, the formation new blood vessels from pre-existing ones, is critical for maintenance of normal cardiovascular physiology. However, excessive or insufficient angiogenesis can contribute to various diseases including cancer, atherosclerosis, and retinopathy. While the mechanism by which angiogenesis occurs is well established, little is known about the mechanisms that negatively regulate this process. Therefore, we investigated the role of mechanosensitive ion channel, TRPV4, in the regulation of angiogenesis by employing in vitro, ex vivo, and in vivo techniques. In the present study, we first cultured aortic ring explants isolated from wild-type (WT) and TRPV4KO mice and found a significant increase in the sprouting from TRPV4KO aortic rings after 5 days. Next, we found that endothelial cells (EC) isolated from TRPV4KO mice (TRPV4KO EC) exhibited increased proliferation, migration, as well as abnormal angiogenesis in vitro, compared to their WT counterparts. Further, in vivo Matrigel plug assays revealed abnormal vascular growth in TRPV4KO mice. Mechanistically, we found that absence of TRPV4 results in a significant increase in basal Rho activity and that pharmacological inhibition of the Rho/Rho kinase pathway was able to normalize the abnormal tube formation exhibited by TRPV4KO EC in vitro . To confirm these findings, we examined tumor growth in TRPV4KO mice treated with Rho kinase inhibitor, Y-27632, and anti-cancer drug Cisplatin, alone and in combination. We found that Y-27632 treatment, in conjunction with Cisplatin but not alone, was able to significantly reduce the abnormal tumor growth seen in TRPV4KO mice, suggesting that Rho kinase inhibition may have normalized the tumor vasculature and improved the delivery of Cisplatin. Taken together, these data suggest that TRPV4 is a negative regulator of angiogenesis and potentially a novel target for pathological and/or therapeutic angiogenesis.
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