{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:29:14Z","timestamp":1792042154093,"version":"4.4.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R35HL155008"],"award-info":[{"award-number":["R35HL155008"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM130459"],"award-info":[{"award-number":["P20GM130459"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS096173"],"award-info":[{"award-number":["R01NS096173"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RF1NS110044"],"award-info":[{"award-number":["RF1NS110044"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R33NS115132"],"award-info":[{"award-number":["R33NS115132"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,31]]},"abstract":"<jats:p>\n                    Gould syndrome is a rare multisystem disorder resulting from autosomal dominant mutations in the collagen-encoding genes\n                    <jats:italic>COL4A1<\/jats:italic>\n                    and\n                    <jats:italic>COL4A2.<\/jats:italic>\n                    Human patients and\n                    <jats:italic>Col4a1<\/jats:italic>\n                    mutant mice display brain pathology that typifies cerebral small vessel diseases (cSVDs), including white matter hyperintensities, dilated perivascular spaces, lacunar infarcts, microbleeds, and spontaneous intracerebral hemorrhage. The underlying pathogenic mechanisms are unknown. Using the\n                    <jats:italic>\n                      Col4a1\n                      <jats:sup>+\/G394V<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model, we found that vasoconstriction in response to internal pressure\u2014the vascular myogenic response\u2014is blunted in cerebral arteries from middle-aged (12 mo old) but not young adult (3 mo old) animals, revealing age-dependent cerebral vascular dysfunction. The defect in the myogenic response was associated with a significant decrease in depolarizing cation currents conducted by TRPM4 (transient receptor potential melastatin 4) channels in native cerebral artery smooth muscle cells (SMCs) isolated from mutant mice. The minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP\n                    <jats:sub>2<\/jats:sub>\n                    ) is necessary for TRPM4 activity. Dialyzing SMCs with PIP\n                    <jats:sub>2<\/jats:sub>\n                    and selective blockade of phosphoinositide 3-kinase (PI3K), an enzyme that converts PIP\n                    <jats:sub>2<\/jats:sub>\n                    to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP\n                    <jats:sub>3<\/jats:sub>\n                    ), restored TRPM4 currents. Acute inhibition of PI3K activity and blockade of transforming growth factor-beta (TGF-\u03b2) receptors also rescued the myogenic response, suggesting that hyperactivity of TGF-\u03b2 signaling pathways stimulates PI3K to deplete PIP\n                    <jats:sub>2<\/jats:sub>\n                    and impair TRPM4 channels. We conclude that age-related cerebral vascular dysfunction in\n                    <jats:italic>\n                      Col4a1\n                      <jats:sup>+\/G394V<\/jats:sup>\n                    <\/jats:italic>\n                    mice is caused by the loss of depolarizing TRPM4 currents due to PIP\n                    <jats:sub>2<\/jats:sub>\n                    depletion, revealing an age-dependent mechanism of cSVD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2217327120","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T13:36:38Z","timestamp":1674567398000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":26,"title":["Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9052-039X","authenticated-orcid":false,"given":"Evan","family":"Yamasaki","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 89557-0318"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8319-5648","authenticated-orcid":false,"given":"Sher","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 89557-0318"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8218-256X","authenticated-orcid":false,"given":"Alfredo","family":"Sanchez Solano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 89557-0318"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratish","family":"Thakore","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno School of Medicine, Reno, NV 89557-0318"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5679-9136","authenticated-orcid":false,"given":"Megan","family":"Smith","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-2240","authenticated-orcid":false,"given":"Cassandre","family":"Labelle-Dumais","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5127-5328","authenticated-orcid":false,"given":"Douglas B.","family":"Gould","sequence":"additional","affiliation":[{"name":"Departments of Ophthalmology, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA 94158"},{"name":"Department of Anatomy, Institute for Human Genetics, Cardiovascular 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