Function and Mechanism of TRPV4 in Promoting Vascular Calcification by Regulating RUNX2 through IL-6

Calcification is an active process where hydroxyapatite crystals deposit in arterial walls or aortic valves, leading to valvular calcification. This study aimed to identify useful molecular markers for vascular calcification and decode the fundamental mechanisms underlying their biological function.

Two published vascular calcification datasets (GSE136593 and GSE159832) from the Gene Expression Omnibus database were downloaded and the data were analyzed using Partek Flow and Qiagen IPA software. We explored the functional expression and pathways of TRPV4 in vascular calcification. A7R5 cells were treated with TRPV4 agonist GSK1016790A (10 nM) and selective TRPV4 antagonist HC067047 (10 µM) for 3 weeks in Dulbecco's modified eagle medium and calcification medium (induced by β-glycerophosphoric acid).

The transcriptomes of calcified and non-calcified blood vessels were found to be significantly distinct. Calcified blood vessels consistently increased TRPV4 expression and regulated the expression of inflammatory factors. TRPV4 was upregulated and strongly correlated with calcification both in human carotid plaque and in mouse carotid artery calcified plaque. TRPV4 promotes osteogenic differentiation and vascular smooth muscle cell calcification induced by β-glycerophosphorus. Western blot and RT-qPCR experiments revealed that TRPV4 promoted smooth muscle cell calcification and osteogenic differentiation by regulating RUNX2 by upregulating IL-6.

TRPV4 regulates vascular calcification by activating IL-6 and suggest potential avenues for the development of interventions to prevent or treat vascular calcification.