Abstract P138: Novel Smooth Muscle Ca 2+ -signaling Nanodomains In Blood Pressure Regulation
| Autor: | Yen-Lin Chen, Zdravka Daneva, Maniselvan Kuppusamy, matteo ottolini, Thomas Baker, Eliska Klimentova, Soham Shah, jennifer sokolowski, Min Park, Swapnil K Sonkusare |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Hypertension. 79 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hyp.79.suppl_1.p138 |
| Popis: | Introduction: Transient receptor potential vanilloid 4 (TRPV4) channel is a crucial Ca 2+ influx pathway in arterial smooth muscle cells (SMCs). However, the effect of SMC TRPV4 (TRPV4 SMC ) channel activity on resting blood pressure has not been investigated. Hypothesis: We hypothesized that SMC TRPV4 (TRPV4 SMC ) channels regulate blood pressure under homeostatic and hypertensive conditions. Results: We provide first evidence that TRPV4 SMC deletion decreases the mean arterial pressure of mice (control: 104.8 ± 2.2 mm Hg; TRPV4 SMC -/- : 101.4 ± 1 mm Hg). α1AR stimulation activated TRPV4 SMC channels through protein kinase Cα (PKCα) signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Surprisingly, intraluminal pressure-induced TRPV4 SMC channel activity opposed vasoconstriction through activation of Ca 2+ -sensitive K + (BK) channels, indicating functionally opposite pools of TRPV4 SMC channels. Superresolution imaging of SMCs revealed spatially separated α1AR:TRPV4 and TRPV4:BK nanodomains in SMCs. These data suggest that spatially separated α1AR-TRPV4 SMC and intraluminal pressure-TRPV4 SMC -BK channel signaling have opposite effects on blood pressure, with α1AR-TRPV4 SMC signaling dominating under resting conditions. Further, in hypertensive patients and a mouse model of hypertension, constrictor α1AR-PKCα-TRPV4 signaling was upregulated, whereas dilator pressure-TRPV4-BK channel signaling was disrupted, thereby increasing vasoconstriction and elevating blood pressure. Conclusions: Collectively, our data identify novel smooth muscle Ca 2+ -signaling nanodomains that regulate blood pressure and demonstrate their impairment in hypertension. |
| Databáze: | OpenAIRE |
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