TRPP2 associates with STIM1 to regulate cerebral vasoconstriction and enhance high salt intake-induced hypertensive cerebrovascular spasm

摘要

Cerebrovascular spasm is a life-threatening event in salt-sensitive hypertension. The relationship between store-operated calcium entry (SOCE) and vasoconstriction in hypertension has not been fully clarified. This study investigated the changes in cerebrovascular contractile responses in high salt intake-induced hypertension and the functional roles of the main components of SOCE, namely, polycystin-2 (TRPP2), stromal interaction molecule 1 (STIM1), and Orai3. Polycystic kidney disease 2 (which encodes TRPP2) knockout mice displayed decreased cerebrovascular SOCE-induced contraction. The blood pressure of age-matched rats fed a normal or high-salt diet for 4 weeks was monitored weekly using noninvasive tail-cuff plethysmography. The systolic blood pressure of the rats fed a high-salt diet was significantly higher than that of controls. Western blotting and immunohistochemical results showed that these hypertensive rats expressed higher levels of cerebrovascular TRPP2, STIM1, and Orai3 than controls. Cerebrovascular tension measurements of the basilar artery indicated that SOCE-mediated contraction was significantly increased in hypertensive rats compared with control rats. In addition, SOCE-mediated contraction was decreased in the basilar arteries of rats pretreated with the SOCE inhibitor BTP-2 (10 mu M) or transfected with TRPP2-specific or STIM1-specific small interfering RNA. Staining with 2,3,5-triphenyltetrazolium chloride (TTC) was used to quantify the infarcted brain area 24 h after middle cerebral artery occlusion, a model of ischemic stroke, in rodents. The infarcted brain area was significantly greater in hypertensive rats and significantly lower in BTP-2-treated rats than in controls. Taken together, these findings indicate that SOCE-induced contraction may be overactive in the basilar arteries of salt-sensitive hypertensive rats, suggesting the dysregulation of TRPP2 and SOCE and its other components.