Crucial role of TRPV2 in the development of hypoxia-induced pulmonary hypertension
K Nakamura, S Akagi, Y Saito, K Ejiri, K Kuroda, M Kanezawa, K Naruse, S Yuasa, Y KatanosakaAbstract
Background
Sustained hypoxia induces pulmonary vasoconstriction, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). However, the precise mechanism by which vasoconstriction leads to vascular remodeling remains to be elucidated. Transient receptor potential cation channel subfamily V member 2 (TRPV2) is a component of native Ca2+-permeable cation channels and a mechanosensor that responds to membrane stretch in vascular smooth muscles.
Purpose
We hypothesized that TRPV2 mediates hypoxic pulmonary vasoconstriction and subsequent vascular remodeling, and tested this using vascular smooth muscle–specific TRPV2-deficient (smTRPV2–/–)mice.
Methods
smTRPV2–/– mice were generated and compared to floxed control mice under hypoxic exposure.
Results
TRPV2 expression was absent in pulmonary artery smooth muscle cells (PASMCs) from smTRPV2–/– mice. Ca2+ responses to cellular stretch and hypoosmotic stimulation were observed in control PASMCs but were impaired in smTRPV2–/– PASMCs, confirming the mechanosensor role of TRPV2 in pulmonary arteries. After 5 weeks of hypoxia, PH and right ventricular hypertrophy were significantly attenuated in smTRPV2–/– mice. Hypoxia-induced full muscularization of pulmonary arteries was also reduced. An MTT assay revealed that hypoxia enhanced proliferation of cultured PASMCs from both groups. However, the rate of hypoxia-induced proliferation of smTRPV2–/– PASMCs was significantly smaller than that of floxed control-PASMCs. Hypoxia signaling pathway PCR array followed by quantitative PCR and Western blot analysis revealed that gene and protein levels of insulin-like growth factor binding protein 3 (IGFBP3) were elevated in TRPV2-deficient-PASMCs and are further increased by hypoxia.
Conclusions
TRPV2 plays a crucial role in the development of hypoxia-induced PH along with an inappropriate increase of PASMCs. The results indicate that TRPV2 is a novel therapeutic target for treatment of hypoxia-induced PH.