Increasing TRPV4 expression restores flow-induced dilation impaired in mesenteric arteries with aging

The flow-stimulated intracellular Ca2+ concentration ([Ca2+](i)) rise in endothelial cells is an important early event leading to flow-induced blood vessel dilation. Transient receptor potential vanilloid subtype 4 (TRPV4), a Ca2+-permeable cation channel, facilitates the flow-stimulated [Ca2+](i) rise. To determine whether TRPV4 is involved in age-related flow-induced blood vessel dilation impairment, we measured blood vessel diameter and nitric oxide (NO) levels and performed Ca2+ imaging, immunoblotting, and immunostaining assays in rats. We found that the flow-induced and TRPV4 activator 4 alpha-PDD-induced dilation of mesenteric arteries from aged rats were significantly decreased compared with those from young rats. The flow-or 4a-PDD-induced [Ca2+](i) rise was also markedly reduced in primary cultured mesenteric artery endothelial cells (MAECs) from aged rats. Immunoblotting and immunostaining results showed an age-related decrease of TRPV4 expression levels in MAECs. Additionally, the 4a-PDD-induced NO production was significantly reduced in aged MAECs. Compared with lentiviral GFP-treated aged rats, lentiviral vector delivery of TRPV4 increased TRPV4 expression level in aged MAECs and restored the flow-and 4a-PDD-induced vessel dilation in aged mesenteric arteries. We concluded that impaired TRPV4-mediated Ca2+ signaling causes endothelial dysfunction and that TRPV4 is a potential target for clinical treatment of age-related vascular system diseases.Natural Science Foundation of China [30800384, 81371284, 81570403]; Anhui Provincial Natural Science Foundation [1301043020, 1108085J11]; Supporting Program for Excellent Young Talents in Universities of Anhui Province; Young Prominent Investigator Supporting Program from Anhui Medical University; National Training Program of Innovation and Entrepreneurship for Undergraduates [AH201410366056, AH201410366078]SCI(E)PubMedARTICLEdujuan@ahmu.edu.cn; shenbing@ahmu.edu.cn22780