CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries
Abstract The arterial myogenic response to intraluminal pressure elicits constriction to maintain tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, tied to L-type (CaV1.2) Ca2+ channels. While important, other Ca2+ channels, particularly T-type could contribute to pressure...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-47715-3 |
| _version_ | 1797452892827811840 |
|---|---|
| author | Mohammed A. El-Lakany Nadia Haghbin Naman Arora Ahmed M. Hashad Galina Yu. Mironova Maria Sancho Robert Gros Donald G. Welsh |
| author_facet | Mohammed A. El-Lakany Nadia Haghbin Naman Arora Ahmed M. Hashad Galina Yu. Mironova Maria Sancho Robert Gros Donald G. Welsh |
| author_sort | Mohammed A. El-Lakany |
| collection | DOAJ |
| description | Abstract The arterial myogenic response to intraluminal pressure elicits constriction to maintain tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, tied to L-type (CaV1.2) Ca2+ channels. While important, other Ca2+ channels, particularly T-type could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca2+ channel (CaV3.1) using C57BL/6 wild type and CaV3.1−/− mice. Patch-clamp electrophysiology, pressure myography, blood pressure and Ca2+ imaging defined the CaV3.1−/− phenotype relative to C57BL/6. CaV3.1−/− mice had absent CaV3.1 expression and whole-cell current, coinciding with lower blood pressure and reduced mesenteric artery myogenic tone, particularly at lower pressures (20–60 mmHg) where membrane potential is hyperpolarized. This reduction coincided with diminished Ca2+ wave generation, asynchronous events of Ca2+ release from the sarcoplasmic reticulum, insensitive to L-type Ca2+ channel blockade (Nifedipine, 0.3 µM). Proximity ligation assay (PLA) confirmed IP3R1/CaV3.1 close physical association. IP3R blockade (2-APB, 50 µM or xestospongin C, 3 µM) in nifedipine-treated C57BL/6 arteries rendered a CaV3.1−/− contractile phenotype. Findings indicate that Ca2+ influx through CaV3.1 contributes to myogenic tone at hyperpolarized voltages through Ca2+-induced Ca2+ release tied to the sarcoplasmic reticulum. This study helps establish CaV3.1 as a potential therapeutic target to control blood pressure. |
| first_indexed | 2024-03-09T15:15:15Z |
| format | Article |
| id | doaj.art-059a78f6dc1a4315ac83ae7dec12006a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:15:15Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-059a78f6dc1a4315ac83ae7dec12006a2023-11-26T13:07:48ZengNature PortfolioScientific Reports2045-23222023-11-0113111510.1038/s41598-023-47715-3CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteriesMohammed A. El-Lakany0Nadia Haghbin1Naman Arora2Ahmed M. Hashad3Galina Yu. Mironova4Maria Sancho5Robert Gros6Donald G. Welsh7Department of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioDepartment of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioDepartment of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioDepartment of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioDepartment of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioDepartment of Physiology, Faculty of Medicine, Complutense University of MadridDepartment of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioDepartment of Physiology & Pharmacology, Schulich School of Medicine, Robarts Research Institute, University of Western OntarioAbstract The arterial myogenic response to intraluminal pressure elicits constriction to maintain tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, tied to L-type (CaV1.2) Ca2+ channels. While important, other Ca2+ channels, particularly T-type could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca2+ channel (CaV3.1) using C57BL/6 wild type and CaV3.1−/− mice. Patch-clamp electrophysiology, pressure myography, blood pressure and Ca2+ imaging defined the CaV3.1−/− phenotype relative to C57BL/6. CaV3.1−/− mice had absent CaV3.1 expression and whole-cell current, coinciding with lower blood pressure and reduced mesenteric artery myogenic tone, particularly at lower pressures (20–60 mmHg) where membrane potential is hyperpolarized. This reduction coincided with diminished Ca2+ wave generation, asynchronous events of Ca2+ release from the sarcoplasmic reticulum, insensitive to L-type Ca2+ channel blockade (Nifedipine, 0.3 µM). Proximity ligation assay (PLA) confirmed IP3R1/CaV3.1 close physical association. IP3R blockade (2-APB, 50 µM or xestospongin C, 3 µM) in nifedipine-treated C57BL/6 arteries rendered a CaV3.1−/− contractile phenotype. Findings indicate that Ca2+ influx through CaV3.1 contributes to myogenic tone at hyperpolarized voltages through Ca2+-induced Ca2+ release tied to the sarcoplasmic reticulum. This study helps establish CaV3.1 as a potential therapeutic target to control blood pressure.https://doi.org/10.1038/s41598-023-47715-3 |
| spellingShingle | Mohammed A. El-Lakany Nadia Haghbin Naman Arora Ahmed M. Hashad Galina Yu. Mironova Maria Sancho Robert Gros Donald G. Welsh CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries Scientific Reports |
| title | CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries |
| title_full | CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries |
| title_fullStr | CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries |
| title_full_unstemmed | CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries |
| title_short | CaV3.1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries |
| title_sort | cav3 1 channels facilitate calcium wave generation and myogenic tone development in mouse mesenteric arteries |
| url | https://doi.org/10.1038/s41598-023-47715-3 |
| work_keys_str_mv | AT mohammedaellakany cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT nadiahaghbin cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT namanarora cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT ahmedmhashad cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT galinayumironova cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT mariasancho cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT robertgros cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries AT donaldgwelsh cav31channelsfacilitatecalciumwavegenerationandmyogenictonedevelopmentinmousemesentericarteries |