Abstract
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 hypoxia-induced 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 receptor-operated 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.
Highlights
The pulmonary circulation is a high-flow, low-resistance and low-pressure circulatory system that differs functionally and structurally from the systemic circulation system, e.g., the coronary circulation system [30, 71]
We examined and compared the protein expression level of STIM1/STIM2 and Orai1/Orai2, which are believed to form SOCC responsible for store-operated Ca2ϩ entry (SOCE), as well as the level of TRPC6, which contributes to forming ROCC, in normoxic control CASMC/pulmonary artery smooth muscle cells (PASMC) with hypoxic CASMC/PASMC
These data imply that it is a unique intrinsic characteristic or feature for PASMC to respond to hypoxia by upregulating cation channels responsible for SOCE/receptor-operated Ca2ϩ entry (ROCE)
Summary
The pulmonary circulation is a high-flow, low-resistance and low-pressure circulatory system that differs functionally and structurally from the systemic circulation system, e.g., the coronary circulation system [30, 71]. A unique aspect of the pulmonary circulation is the vasoconstrictor response to hypoxia, whereas systemic arteries undergo dilation [15, 56, 57]. Persistent and widespread hypoxia throughout the lung, as occurring in patients with chronic obstructive pulmonary disease and obstructive sleep apnea or in residents living at high altitude, results in hypoxic pulmonary hypertension (HPH) by inducing sustained pulmonary vasoconstriction and pulmonary vascular medial hypertrophy. The cellular and molecular mechanisms underlying the diverse cellular responses in pulmonary and systemic (e.g., coronary) artery smooth muscle cells, are still not clearly understood despite the vast efforts of investigators to elucidate the mechanism
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