Journal
HYPERTENSION RESEARCH
Volume 41, Issue 7, Pages 506-514Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41440-018-0045-1
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Funding
- JSPS KAKENHI [26860547]
- Charitable Trust Araki Medical and Biochemical Research Memorial Fund
- Japan Foundation for Applied Enzymology
- Research Foundation for Community Medicine
- SENSHIN Medical Research Foundation
- Takeda Pharmaceutical Co. Ltd.
- Novartis Pharma KK
- Grants-in-Aid for Scientific Research [26860547] Funding Source: KAKEN
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In vascular endothelial cells, store-operated calcium entry (SOCE) activates endothelial NO synthase (eNOS) and regulates nitric oxide (NO) production as well as flow-dependent mechanical stimuli. Stromal interaction molecule 1, or STIM1, was recently identified to be essential for SOCE, acting as a calcium sensor for intracellular calcium stores. However, how STIM1 affects endothelial function and blood pressure (BP) remains unclear. We generated STIM1 fl/fl mice and vascular endothelial cell-specific STIM1 knockout mice using the Cre-loxP system, and conducted experiments using these mice to clarify the physiological role of STIM1 in vascular endothelial function and BP as follows: (1) SOCE was analyzed in isolated aortic endothelial cells by calcium add-back with fluorescent Ca2+ indicators. Phosphorylation of eNOS and NO production were evaluated by immunoblotting and the NO indicator, respectively. (2) Tension of aortic rings was measured in 10-week-old mice in response to acetylcholine. (3) BP was measured in 10-week-old mice by the telemetry system. The results were: (1) SOCE, eNOS activation, and NO production were suppressed by similar to 50-60% in endothelial cells from STIM1 knockout. (2) Endothelium-dependent vasodilation was decreased in aortic rings from STIM1 knockout mice, whereas endothelium-independent relaxation was not altered. (3) STIM1 knockout mice exhibited significant BP elevation, especially in nighttime. (124.3 +/- 2.5/99.2 +/- 3.9 vs. 114.1 +/- 3.2/83.6 +/- 1.7 (nighttime, mmHg), 109.7 +/- 1.7/83.0 +/- 3.0 vs. 104.8 +/- 3.3/73.7 +/- 1.6 (daytime, mmHg), knockout vs. control, respectively). In conclusion, STIM1 in vascular endothelial cell modulates vascular function through NO production and has a major role in regulating BP, especially in the active time.
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