The transient receptor potential vanilloid‐3 regulates hypoxia‐mediated pulmonary artery smooth muscle cells proliferation via PI3K/AKT signaling pathway

Objectves Transient receptor potential vanilloid 3 ( TRPV 3) is a member of the TRP channels family of Ca 2+ ‐permeant cation channels. In this study, we aim to investigate the role of TRPV 3 in pulmonary vascular remodeling and PASMC s proliferation under hypoxia. Materials and methods The expression of TRPV 3 was evaluated in patients with pulmonary arterial hypertension ( PAH ) and hypoxic rats, using hematoxylin and eosin (H&E) and immunohistochemistry. In vitro, MTT assay, flow cytometry, Western blotting and immunofluorescence were performed to investigate the effects of TRPV 3 on proliferation of PASMC s. Results We found that, in vivo, the expression of TRPV 3 was increased in patients with PAH and hypoxic rats. Right ventricular hypertrophy measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length ( HW / TL ), the right ventricle/left ventricle plus septum ( RV / LV +S) and the medial width of the pulmonary artery were increased in chronic hypoxic rats. Moreover, the expression of proliferating cell nuclear antigen ( PCNA ), Cyclin D, Cyclin E and Cyclin A, phospho‐CaMKII (p‐CaMKII) were induced by hypoxia. In vitro, we revealed that hypoxia promoted PASMCs viability, increased the expression of PCNA , Cyclin D, Cyclin E, Cyclin A p‐Ca MKII , made more cells from G 0 /G 1 phase to G 2 /M + S phase, enhanced the microtubule formation, and increased [Ca 2+ ] i , which could be suppressed by Ruthenium Red, an inhibitor of TRPV 3, and TRPV 3 silencing has similar effects. Furthermore, the up‐regulated expression of PCNA , Cyclin D, Cyclin E and Cyclin A, the increased number of cells in G 2 /M and S phase, and the enhanced activation and expression of PI 3K and AKT proteins induced by hypoxia and in presence of carvacrol (an agonist of TRPV 3), was significantly attenuated by incubation of LY 294002, a specific inhibitor for PI 3K/ AKT . Conclusions These findings suggest that TRPV 3 is involved in hypoxia‐induced pulmonary vascular remodeling and promotes proliferation of PASMC s and the effect is, at least in part, mediated via the PI 3K/ AKT pathway.