Hypoxia selectively upregulates cation channels and increases cytosolic [Ca²⁺] in pulmonary, but not coronary, arterial smooth muscle cells

Ca²⁺ signaling, particularly the mechanism via store-operated Ca²⁺ entry (SOCE) and receptor-operated Ca²⁺ entry (ROCE), plays a critical role in the development of acute hypoxiainduced pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension. This study aimed to test the hypothesis that chronic hypoxia differentially regulates the expression of proteins that mediate SOCE and ROCE [stromal interacting molecule (STIM), Orai, and canonical transient receptor potential channel TRPC6] in pulmonary (PASMC) and coronary (CASMC) artery smooth muscle cells. The resting cytosolic [Ca²⁺] ([Ca²⁺]_cyt) and the stored [Ca²⁺] in the sarcoplasmic reticulum were not different in CASMC and PASMC. Seahorse measurement showed a similar level of mitochondrial bioenergetics (basal respiration and ATP production) between CASMC and PASMC. Glycolysis was significantly higher in PASMC than in CASMC. The amplitudes of cyclopiazonic acid-induced SOCE and OAG-induced ROCE in CASMC are slightly, but significantly, greater than in PASMC. The frequency and the area under the curve of Ca²⁺ oscillations induced by ATP and histamine were also larger in CASMC than in PASMC. Na⁺/Ca²⁺ exchanger-mediated increases in [Ca²⁺]_cyt did not differ significantly between CASMC and PASMC. The basal protein expression levels of STIM1/2, Orai1/2, and TRPC6 were higher in CASMC than in PASMC, but hypoxia (3% O₂ for 72 h) significantly upregulated protein expression levels of STIM1/STIM2, Orai1/Orai2, and TRPC6 and increased the resting [Ca²⁺]_cyt only in PASMC, but not in CASMC. The different response of essential components of store-operated and receptoroperated Ca²⁺ channels to hypoxia is a unique intrinsic property of PASMC, which is likely one of the important explanations why hypoxia causes pulmonary vasoconstriction and induces pulmonary vascular remodeling, but causes coronary vasodilation.