{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:52:36Z","timestamp":1791287556963,"version":"4.1.0"},"posted":{"date-parts":[[2026,10,1]]},"group-title":"Physiology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH\/NHLBI","award":["R35HL155008"],"award-info":[{"award-number":["R35HL155008"]}]},{"name":"NIH\/NHLBI","award":["R01HL122770"],"award-info":[{"award-number":["R01HL122770"]}]},{"name":"NIH\/NINDS","award":["RF1NS148111"],"award-info":[{"award-number":["RF1NS148111"]}]},{"name":"NIH\/NINDS","award":["R01NS140370"],"award-info":[{"award-number":["R01NS140370"]}]},{"name":"NIH\/NIA","award":["R01AG097446"],"award-info":[{"award-number":["R01AG097446"]}]},{"name":"NIH\/NIDDK","award":["R01DK135621"],"award-info":[{"award-number":["R01DK135621"]}]},{"name":"NIH\/NEI","award":["P30EY037668"],"award-info":[{"award-number":["P30EY037668"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pathogenic variants of\n                  <jats:italic>COL4A1<\/jats:italic>\n                  and\n                  <jats:italic>COL4A2<\/jats:italic>\n                  , which encode the \u03b11 and \u03b12 chains of type IV collagen in vascular basement membranes, cause cerebral small vessel disease and intracerebral hemorrhage, but the signaling mechanisms that precede vascular damage remain incompletely defined. Here, we investigated cerebral arterial function in mice heterozygous for the\n                  <jats:italic>\n                    Col4a2\n                    <jats:sup>+\/G646D<\/jats:sup>\n                  <\/jats:italic>\n                  mutation. Cerebral pial arteries from aged (12-month-old), but not young (3-month-old),\n                  <jats:italic>\n                    Col4a2\n                    <jats:sup>+\/G646D<\/jats:sup>\n                  <\/jats:italic>\n                  mice exhibited impaired pressure-induced myogenic tone, whereas downstream parenchymal arterioles retained normal myogenic responsiveness, revealing a segment-selective vascular defect. The frequency of subcellular Ca\n                  <jats:sup>2+<\/jats:sup>\n                  signals (Ca\n                  <jats:sup>2+<\/jats:sup>\n                  sparks) generated by the release of Ca\n                  <jats:sup>2+<\/jats:sup>\n                  through ryanodine receptors (RyR2s) on the sarcoplasmic reticulum (SR) was increased, and large-conductance Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -activated K\n                  <jats:sup>+<\/jats:sup>\n                  (BK) channel activity was elevated, in cerebral pial artery smooth muscle cells (SMCs) from aged\n                  <jats:italic>\n                    Col4a2\n                    <jats:sup>+\/G646D<\/jats:sup>\n                  <\/jats:italic>\n                  mice. SR Ca\n                  <jats:sup>2+<\/jats:sup>\n                  store load and\n                  <jats:italic>Ryr2<\/jats:italic>\n                  transcript abundance were unchanged in these cells, but Stimulated Emission Depletion super-resolution microscopy revealed that RyR2 protein clusters were enlarged compared with controls. Protein kinase A (PKA) activation reproduced RyR2 cluster enlargement, whereas PKA inhibition normalized RyR2 cluster organization and BK channel activity in SMCs from aged\n                  <jats:italic>\n                    Col4a2\n                    <jats:sup>+\/G646D<\/jats:sup>\n                  <\/jats:italic>\n                  mice. These findings identify age-associated, PKA-dependent, nanoscale remodeling of RyR2 clusters as a previously unknown mechanism underlying cerebral arterial dysfunction in COL4A2-related disease.\n                <\/jats:p>","DOI":"10.64898\/2026.09.25.754477","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:55:11Z","timestamp":1790898911000},"source":"Crossref","is-referenced-by-count":0,"title":["Ryanodine receptor cluster remodeling links\n                  <i>COL4A2<\/i>\n                  mutation to cerebral artery dysfunction"],"prefix":"10.64898","author":[{"given":"Boris","family":"Lavanderos","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14624, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Nevada Reno, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Sanchez-Solano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14624, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanchun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14624, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandre","family":"Labelle-Dumais","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Feng Earley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14624, USA"},{"name":"Department of Medicine, University of Rochester Medical Center, Rochester, NY 14624, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas B.","family":"Gould","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA 94158, USA"},{"name":"Department of Anatomy, Institute for Human Genetics, Cardiovascular Research Institute, Bakar Aging Research Institute, UCSF School of Medicine, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9560-2941","authenticated-orcid":false,"given":"Scott","family":"Earley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14624, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"3","key":"2026100604101009000_2026.09.25.754477v1.1","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1152\/physrev.00028.2024","article-title":"The pathogenesis of cerebral small vessel disease and vascular cognitive impairment","volume":"105","year":"2025","journal-title":"Physiol Rev"},{"key":"2026100604101009000_2026.09.25.754477v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70104-6"},{"key":"2026100604101009000_2026.09.25.754477v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.113.002878"},{"key":"2026100604101009000_2026.09.25.754477v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2015.62"},{"key":"2026100604101009000_2026.09.25.754477v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109418"},{"key":"2026100604101009000_2026.09.25.754477v1.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa053727"},{"key":"2026100604101009000_2026.09.25.754477v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.110.581918"},{"key":"2026100604101009000_2026.09.25.754477v1.8","doi-asserted-by":"crossref","first-page":"108365","DOI":"10.1016\/j.yebeh.2021.108365","article-title":"Epilepsy and related challenges in children with COL4A1 and COL4A2 mutations: A Gould syndrome patient registry","volume":"125","year":"2021","journal-title":"Epilepsy Behav"},{"key":"2026100604101009000_2026.09.25.754477v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-025-00982-x"},{"key":"2026100604101009000_2026.09.25.754477v1.10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.pediatrneurol.2026.06.025","article-title":"The Expanding Phenotypic Spectrum of COL4A1- and COL4A2-Related Disorders: A Systematic Review","volume":"183","year":"2026","journal-title":"Pediatr Neurol"},{"issue":"4","key":"2026100604101009000_2026.09.25.754477v1.11","doi-asserted-by":"crossref","first-page":"e32099","DOI":"10.1002\/ajmg.c.32099","article-title":"Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol","volume":"196","year":"2024","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"2026100604101009000_2026.09.25.754477v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2016.10.003"},{"issue":"9","key":"2026100604101009000_2026.09.25.754477v1.13","doi-asserted-by":"crossref","first-page":"101514","DOI":"10.1016\/j.gim.2025.101514","article-title":"COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management","volume":"27","year":"2025","journal-title":"Genet Med"},{"key":"2026100604101009000_2026.09.25.754477v1.14","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.025629"},{"key":"2026100604101009000_2026.09.25.754477v1.15","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001309"},{"key":"2026100604101009000_2026.09.25.754477v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(21)00031-4"},{"issue":"5","key":"2026100604101009000_2026.09.25.754477v1.17","doi-asserted-by":"crossref","first-page":"e2217327120","DOI":"10.1073\/pnas.2217327120","article-title":"Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome","volume":"120","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026100604101009000_2026.09.25.754477v1.18","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adi3966"},{"key":"2026100604101009000_2026.09.25.754477v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306479120"},{"key":"2026100604101009000_2026.09.25.754477v1.20","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00053.2021"},{"key":"2026100604101009000_2026.09.25.754477v1.21","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000147311.54833.03"},{"key":"2026100604101009000_2026.09.25.754477v1.22","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004732"},{"key":"2026100604101009000_2026.09.25.754477v1.23","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.107.483404"},{"key":"2026100604101009000_2026.09.25.754477v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.11.022"},{"key":"2026100604101009000_2026.09.25.754477v1.25","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013395"},{"key":"2026100604101009000_2026.09.25.754477v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1420765112"},{"key":"2026100604101009000_2026.09.25.754477v1.27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01021.2020"},{"issue":"17","key":"2026100604101009000_2026.09.25.754477v1.28","doi-asserted-by":"crossref","first-page":"166665","DOI":"10.1016\/j.jmb.2020.09.024","article-title":"Small Molecular Inhibitors Block TRPM4 Currents in Prostate Cancer Cells, with Limited Impact on Cancer Hallmark Functions","volume":"433","year":"2021","journal-title":"J Mol Biol"},{"key":"2026100604101009000_2026.09.25.754477v1.29","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00550.2009"},{"key":"2026100604101009000_2026.09.25.754477v1.30","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5236.633"},{"key":"2026100604101009000_2026.09.25.754477v1.31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.211br.x"},{"key":"2026100604101009000_2026.09.25.754477v1.32","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.113.2.229"},{"key":"2026100604101009000_2026.09.25.754477v1.33","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.025197"},{"key":"2026100604101009000_2026.09.25.754477v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(01)75741-4"},{"key":"2026100604101009000_2026.09.25.754477v1.35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908971106"},{"key":"2026100604101009000_2026.09.25.754477v1.36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1804593115"},{"key":"2026100604101009000_2026.09.25.754477v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2018.12.017"},{"key":"2026100604101009000_2026.09.25.754477v1.38","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.113.2.177"},{"key":"2026100604101009000_2026.09.25.754477v1.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004417"},{"key":"2026100604101009000_2026.09.25.754477v1.40","doi-asserted-by":"crossref","unstructured":"Krishnan V , Ali S , Gonzales AL , Thakore P , Griffin CS , Yamasaki E , et al. STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells. Elife. 2022;11.","DOI":"10.7554\/eLife.70278"},{"key":"2026100604101009000_2026.09.25.754477v1.41","doi-asserted-by":"publisher","DOI":"10.1364\/OL.19.000780"},{"key":"2026100604101009000_2026.09.25.754477v1.42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010126"},{"issue":"5","key":"2026100604101009000_2026.09.25.754477v1.43","doi-asserted-by":"crossref","first-page":"C1346","DOI":"10.1152\/ajpcell.1998.274.5.C1346","article-title":"Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides","volume":"274","year":"1998","journal-title":"Am J Physiol"},{"key":"2026100604101009000_2026.09.25.754477v1.44","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2001.281.3.C1029"},{"key":"2026100604101009000_2026.09.25.754477v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.03.015"},{"key":"2026100604101009000_2026.09.25.754477v1.46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510113103"},{"key":"2026100604101009000_2026.09.25.754477v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/s0021-9258(18)81864-6"},{"key":"2026100604101009000_2026.09.25.754477v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2014.139"},{"key":"2026100604101009000_2026.09.25.754477v1.49","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-061121-040127"},{"key":"2026100604101009000_2026.09.25.754477v1.50","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.040963"},{"key":"2026100604101009000_2026.09.25.754477v1.51","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00022.2021"},{"key":"2026100604101009000_2026.09.25.754477v1.52","doi-asserted-by":"crossref","unstructured":"Galice S , Xie Y , Yang Y , Sato D , and Bers DM . Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release. J Am Heart Assoc. 2018;7(13).","DOI":"10.1161\/JAHA.118.008724"},{"key":"2026100604101009000_2026.09.25.754477v1.53","doi-asserted-by":"crossref","unstructured":"Shen X , van den Brink J , Bergan-Dahl A , Kolstad TR , Norden ES , Hou Y , et al. Prolonged \u03b2-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure. Elife. 2022;11.","DOI":"10.7554\/eLife.77725"},{"key":"2026100604101009000_2026.09.25.754477v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2017.01.015"},{"key":"2026100604101009000_2026.09.25.754477v1.55","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.303897"},{"key":"2026100604101009000_2026.09.25.754477v1.56","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.007423"},{"key":"2026100604101009000_2026.09.25.754477v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14040-1"},{"key":"2026100604101009000_2026.09.25.754477v1.58","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005347"},{"key":"2026100604101009000_2026.09.25.754477v1.59","doi-asserted-by":"crossref","unstructured":"Kakogiannos N , Scalise AA , Martini E , Maderna C , Benvenuto AF , D\u2019Antonio M , et al. GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system. J Clin Invest. 2024;134(15).","DOI":"10.1172\/JCI165368"},{"key":"2026100604101009000_2026.09.25.754477v1.60","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.106.064733"},{"key":"2026100604101009000_2026.09.25.754477v1.61","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt560"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.25.754477","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:10:22Z","timestamp":1791285022000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.25.754477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":61,"URL":"https:\/\/doi.org\/10.64898\/2026.09.25.754477","relation":{},"subject":[],"published":{"date-parts":[[2026,10,1]]},"subtype":"preprint"}}