Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition
Abstract We previously demonstrated that the inability of primary endothelial cilia to sense fluid shear stress can lead to nitric oxide (NO) deficiency and cause hypertension (HTN). Decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in Alzheimer’s disease (AD) patients through...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87212-3 |
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| author | Hannah C. Saternos Kathleen V. Forero Mahmood A. Meqdad Raghad Buqaileh Clare L. Sunderman Gillian Gallagher William S. Messer Ashraf M. Mohieldin Claudio A. Mucci Sanjana Kumariya Islam A. Osman James P. Burkett Wissam A. AbouAlaiwi |
| author_facet | Hannah C. Saternos Kathleen V. Forero Mahmood A. Meqdad Raghad Buqaileh Clare L. Sunderman Gillian Gallagher William S. Messer Ashraf M. Mohieldin Claudio A. Mucci Sanjana Kumariya Islam A. Osman James P. Burkett Wissam A. AbouAlaiwi |
| author_sort | Hannah C. Saternos |
| collection | DOAJ |
| description | Abstract We previously demonstrated that the inability of primary endothelial cilia to sense fluid shear stress can lead to nitric oxide (NO) deficiency and cause hypertension (HTN). Decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in Alzheimer’s disease (AD) patients through increased deposition of amyloid beta (Aβ). However, the molecular mechanisms underlying the pathogenesis of HTN and AD are incompletely understood. The objective of this study was to examine the pathophysiological roles of vascular primary cilia and muscarinic acetylcholine receptor 3 (CHRM3) in HTN and AD. We discovered, for the first time, that CHRM3 was localized to primary cilia of endothelial and cerebrovascular cells, and that CHRM3 expression was downregulated in cilialess cells. Moreover, CHRM3 activation enhanced cilia length and sensory function in terms of eNOS activation. To further examine the role of vascular CHRM3 in vivo, we showed that endothelial CHRM3 knockout was associated with increased BP and attenuated acetylcholine-mediated vascular relaxation. In addition, endothelial CHRM3 knockout resulted in altered fear behavior. This demonstrates the physiological significance of endothelial CHRM3 signaling and primary cilia-derived NO production as an important mechanism in the control of BP and cognition. |
| format | Article |
| id | doaj-art-8f93d894681f48229a52ee676f47604c |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-8f93d894681f48229a52ee676f47604c2025-02-02T12:18:04ZengNature PortfolioScientific Reports2045-23222025-01-0115112110.1038/s41598-025-87212-3Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognitionHannah C. Saternos0Kathleen V. Forero1Mahmood A. Meqdad2Raghad Buqaileh3Clare L. Sunderman4Gillian Gallagher5William S. Messer6Ashraf M. Mohieldin7Claudio A. Mucci8Sanjana Kumariya9Islam A. Osman10James P. Burkett11Wissam A. AbouAlaiwi12Department of Neurosurgery, University of Colorado Anschutz Medical CampusDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoMaster of Pharmaceutical Sciences Department, College of Graduate Studies, California Northstate UniversityDepartment of Biological Sciences, College of Natural Sciences and Mathematics, The University of ToledoDepartment of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of ToledoDepartment of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of ToledoDepartment of Neurosciences, College of Medicine and Life Sciences, The University of ToledoDepartment of Pharmacology and Experimental Therapeutics; MS 1015, College of Pharmacy and Pharmaceutical Sciences, The University of ToledoAbstract We previously demonstrated that the inability of primary endothelial cilia to sense fluid shear stress can lead to nitric oxide (NO) deficiency and cause hypertension (HTN). Decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in Alzheimer’s disease (AD) patients through increased deposition of amyloid beta (Aβ). However, the molecular mechanisms underlying the pathogenesis of HTN and AD are incompletely understood. The objective of this study was to examine the pathophysiological roles of vascular primary cilia and muscarinic acetylcholine receptor 3 (CHRM3) in HTN and AD. We discovered, for the first time, that CHRM3 was localized to primary cilia of endothelial and cerebrovascular cells, and that CHRM3 expression was downregulated in cilialess cells. Moreover, CHRM3 activation enhanced cilia length and sensory function in terms of eNOS activation. To further examine the role of vascular CHRM3 in vivo, we showed that endothelial CHRM3 knockout was associated with increased BP and attenuated acetylcholine-mediated vascular relaxation. In addition, endothelial CHRM3 knockout resulted in altered fear behavior. This demonstrates the physiological significance of endothelial CHRM3 signaling and primary cilia-derived NO production as an important mechanism in the control of BP and cognition.https://doi.org/10.1038/s41598-025-87212-3 |
| spellingShingle | Hannah C. Saternos Kathleen V. Forero Mahmood A. Meqdad Raghad Buqaileh Clare L. Sunderman Gillian Gallagher William S. Messer Ashraf M. Mohieldin Claudio A. Mucci Sanjana Kumariya Islam A. Osman James P. Burkett Wissam A. AbouAlaiwi Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition Scientific Reports |
| title | Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition |
| title_full | Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition |
| title_fullStr | Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition |
| title_full_unstemmed | Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition |
| title_short | Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition |
| title_sort | muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition |
| url | https://doi.org/10.1038/s41598-025-87212-3 |
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