Key result
Smooth muscle TRPV2 deficiency attenuates hypoxia-induced pulmonary hypertension and right ventricular hypertrophy.
Why the study?
Sustained hypoxia induces pulmonary vasoconstriction and pulmonary hypertension, but the precise mechanism by which vasoconstriction leads to vascular remodeling remained to be elucidated.
Does vascular smooth muscle-specific TRPV2 deficiency attenuate hypoxia-induced pulmonary hypertension and vascular remodeling in mice?
Does vascular smooth muscle-specific TRPV2 deficiency attenuate hypoxia-induced pulmonary hypertension and vascular remodeling in mice?
Vascular smooth muscle TRPV2 plays a crucial mechanosensory role in mediating hypoxia-induced pulmonary hypertension and PASMC proliferation in mice, identifying TRPV2 as a potential novel therapeutic target for pulmonary hypertension.
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.
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Nakamura et al. (2026) studied Hypoxia-induced pulmonary hypertension. Vascular smooth muscle–specific TRPV2 deficiency (smTRPV2–/–) vs. Floxed control mice was evaluated on Hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary artery muscularization. Vascular smooth muscle-specific TRPV2 deficiency significantly attenuated pulmonary hypertension, right ventricular hypertrophy, and arterial muscularization in mice after 5 weeks of hypoxia.
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