The Role Of TRPM8Channels In Regulation Of Pulmonary Arterial Smooth Muscle And Their Function In The Development Of Pulmonary Hypertension

Objective: The typical vascular pathological states in the development ofpulmonary hypertension （PH） are due to Ca²⁺homeostasis imbalance in pulmonaryvascular smooth muscle cells （PASMCs）. In the present study, PH rats were simulatedby means of monocrotaline–injection （MCT） and chronic hypoxia （CH） to reflectdifferent PH characteristics. Identified the changes of TRPM8expression and functionin pulmonary arteries （PAs） through different PH models and which mainly aimed toprovide a newer target for PH prevention and treatment.Methods: A dose of50mg/kg （BW） MCT was given to SD rats by singleintraperitoneal injection as MCT-group and another model was exposured with CH（10%oxygen） within21days. The observation items: mean right ventricular pressure（mRVP）; right ventricular mass index （RVMI）; TRPM8mRNA and protein expressedin PAs; the relationship between the time courses of hemodynamics indexes （mRVP,RVMI） and TRPM8mRNA expression in the development of differnet PH types;1³00μM Menthol effected on the tension of de-endothelial PAs upon baseline stateand phenylephrine （PHEN） pre-contraction.Results: It was shown that the highest mRVP and RVMI in MCT-group with thelowest TRPM8expression, the moderate in CH-group, and the lowest mRVP andRVMI in CON with the highest TRPM8expression; TRPM8mRNA in CH-groupreduced to minimum level after1d simulated, which was begun to down-regulated on7d after MCT-injection, when the expression level was declined to minimum, itsubsequently changed little; in contrast with TRPM8expression, the alteration ofmRVP and RVMI increased in the course of PH and which happened latter than TRPM8changed in both MCT-and CH-group; the results suggested that MCT andCH affect the TRPM8mRNA at first, followed mRVP increased and which couldcause the compensatory right ventricular hypertrophy; vasoconstriction with PHENcould be inhibited by1μM³00μM Menthol and which was significantly larger thanthe basal tension declined; the dose-dependent curves presented a left shift in PAs ofCH-group than CON-and MCT-groups.Conclusion: The activation of TRPM8channels can obviously relieve thevascular contraction. Down-regulation of TRPM8might be an adaption for PAssustained contraction in the pathogenesis of PH, and TRPM8may play a role ofprotective factor to against the injury caused by PH. A modest decline of TRPM8willadvantage the reduction of the Ca²⁺influx and relaxation of vascular smooth muscletension. On the other hand, the interaction of TRPM8and BKCa cause thedown-regulation of vascular tension. In the course of PH, proper adjustments forTRPM8expression may help to maintain the calcium homeostasis in PASMCs andregress the progress of PH. The results of present study provide a new target for thetreatment and prevention of PH.