{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:55:30Z","timestamp":1781758530936,"version":"3.54.5"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Fujian Province, China","award":["2024J011338"],"award-info":[{"award-number":["2024J011338"]}]},{"name":"Xiamen Municipal Medical and Health Guiding Projects, China","award":["3502Z20224ZD1045"],"award-info":[{"award-number":["3502Z20224ZD1045"]}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Protein arginine methyltransferase 5 (PRMT5) regulates vascular smooth muscle cell (VSMC) phenotype switching to participate in cardiovascular disease progression. This study aimed to explore the effect of EPZ015666, a PRMT5 enzymatic activity inhibitor, on VSMC behaviors and phenotype switching in intracranial aneurysm (IA), and potential mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>IA rat model was established by ligating left common carotid artery and right renal artery, followed by elastase injection and angiotensin II (Ang II) infusion. Rat brain artery VSMCs were treated with 1\u202f\u03bcM Ang II to establish the IA cell model. Then, cells were treated with 10\u202f\u03bcM EPZ015666 in combination with Ang II. Furthermore, cells were co-administered with Ang II, EPZ015666, and 50\u202f\u03bcg\/mL 740Y-P [phosphoinositide 3-kinase (PI3K) agonist].<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PRMT5 was increased in the IA specimens of rats and Ang II-treated VSMCs. In Ang II-treated VSMCs, EPZ015666 did not affect PRMT5 but decreased H4R3me2s, suggesting its inhibition of PRMT5 enzymatic activity. EPZ015666 increased VSMC apoptosis, decreased viability, and reduced invasive capacity. EPZ015666 increased\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -smooth muscle actin and decreased osteopontin and matrix metalloproteinase-9, which indicated that EPZ015666 facilitated the VSMC transition from synthetic phenotype to contractile phenotype. EPZ015666 decreased phosphorylated (p)-PI3K and p-protein kinase B (AKT), suggesting its inhibition of PI3K\/AKT pathway. 740Y-P reversed the impact of EPZ015666 on Ang II-treated VSMCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>EPZ015666 inhibits the PI3K\/AKT pathway to promote VSMC phenotype switching from synthetic phenotype to contractile phenotype, thereby attenuating IA progression. However, this study is limited by the use of male-only rats a relatively small sample size, which may restrict the generalizability of the findings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1771196","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:35:33Z","timestamp":1781757333000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["PRMT5 inhibition suppresses the PI3K\/AKT pathway to attenuate vascular smooth muscle cell pathological phenotype in intracranial aneurysm"],"prefix":"10.3389","volume":"17","author":[{"given":"Junlong","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, 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University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjiang","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of 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