Role of Cholesterol in the Regulation of Hydrogen Sulfide Signaling within the Vascular Endothelium
H<sub>2</sub>S is a gaseous signaling molecule enzymatically produced in mammals and H<sub>2</sub>S-producing enzymes are expressed throughout the vascular wall. We previously reported that H<sub>2</sub>S-induced vasodilation is mediated through transient receptor...
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Main Authors: | , , , , |
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Format: | Book |
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MDPI AG,
2022-08-01T00:00:00Z.
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Summary: | H<sub>2</sub>S is a gaseous signaling molecule enzymatically produced in mammals and H<sub>2</sub>S-producing enzymes are expressed throughout the vascular wall. We previously reported that H<sub>2</sub>S-induced vasodilation is mediated through transient receptor potential cation channel subfamily V member 4 (TRPV4) and large conductance (BK<sub>Ca</sub>) potassium channels; however, regulators of this pathway have not been defined. Previous reports have shown that membrane cholesterol limits activity of TRPV4 and BK<sub>Ca</sub> potassium channels. The current study examined the ability of endothelial cell (EC) plasma membrane (PM) cholesterol to regulate H<sub>2</sub>S-induced vasodilation. We hypothesized that EC PM cholesterol hinders H<sub>2</sub>S-mediated vasodilation in large mesenteric arteries. In pressurized, U46619 pre-constricted mesenteric arteries, decreasing EC PM cholesterol in large arteries using methyl-β-cyclodextrin (MBCD, 100 µM) increased H<sub>2</sub>S-induced dilation (NaHS 10, 100 µM) but MBCD treatment had no effect in small arteries. <i>Enface</i> fluorescence showed EC PM cholesterol content is higher in large mesenteric arteries than in smaller arteries. The NaHS-induced vasodilation following MBCD treatment in large arteries was blocked by TRPV4 and BK<sub>Ca</sub> channel inhibitors (GSK219384A, 300 nM and iberiotoxin, 100 nM, respectively). Immunohistochemistry of mesenteric artery cross-sections show that TRPV4 and BK<sub>Ca</sub> are both present in EC of large and small arteries. Cholesterol supplementation into EC PM of small arteries abolished NaHS-induced vasodilation but the cholesterol enantiomer, epicholesterol, had no effect. Proximity ligation assay studies did not show a correlation between EC PM cholesterol content and the association of TRPV4 and BK. Collectively, these results demonstrate that EC PM cholesterol limits H<sub>2</sub>S-induced vasodilation through effects on EC TRPV4 and BK<sub>Ca</sub> channels. |
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Item Description: | 10.3390/antiox11091680 2076-3921 |