miR-18a-5p upregulates Orai1 expression to promote vascular smooth muscle cell proliferation and neointimal hyperplasia after injury.

Martin-Bornez, M.; Dominguez-Liste, B.; Avila-Medina, J.; de Rojas-de Pedro, E. S.; Galeano-Otero, I.; Sanchez-Collado, J.; Ordonez-Fernandez, A.; Rosado, J. A.; Hmadcha, A.; Falcon, D.; Smani, T.

doi:10.64898/2026.01.20.700592

bioRxiv · 10.64898/2026.01.20.700592

miR-18a-5p upregulates Orai1 expression to promote vascular smooth muscle cell proliferation and neointimal hyperplasia after injury.

Martin-Bornez, M.·Dominguez-Liste, B.·Avila-Medina, J.·de Rojas-de Pedro, E. S.·Galeano-Otero, I.·Sanchez-Collado, J.·Ordonez-Fernandez, A.·Rosado, J. A.·Hmadcha, A.·Falcon, D.·Smani, T.

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Abstract

RationaleNeointimal hyperplasia, a key contributor to restenosis, is driven by the abnormal proliferation and migration of vascular smooth muscle cells (VSMC), although the underlying molecular mechanisms remain incompletely understood. This study aimed to characterize the structural, transcriptomic, and post-transcriptional changes driving neointima formation, with a focus on store-operated calcium entry (SOCE) pathways and microRNA (miRNA) regulation. MethodsA rat carotid angioplasty model was employed to assess neointimal development at 1, 2, and 3 weeks post-injury. VSMC isolated from rat coronary arteries and A7r5 VSMC line were used to assess intracellular Ca2+ dynamics, and expression of gene and protein. ResultsProgressive neointimal thickening and impaired contractility were observed after carotid artery injury, accompanied by significant VSMC proliferation. Transcriptomic profiling revealed differentially expressed genes (DEGs) at 1 and 3 weeks, with enrichment in pathways related to cell cycle, migration, and Ca2+ signaling. Among Ca2+ -regulatory genes, Orai1 and SARAF were upregulated in the neointima and shown to colocalize and interact post-injury. Functional studies in VSMC demonstrated that Orai1, but not SARAF, is involved in insulin-like growth factor 1 (IGF-1)-induced proliferation and SOCE activation. Moreover, miRNA profiling identified miR-18a-5p, from the miR-17-92 cluster, as the most upregulated miRNA early post-injury. miR-18a-5p unusually enhanced Orai1 promoter activity and protein expression, leading to increased SOCE in VSMC. In human coronary arteries from ischemic hearts Orai1 was upregulated, suggesting the potential translational relevance of Orai1 in vascular pathology. ConclusionsOur findings identify miR-18a-5p as a novel positive regulator of Orai1 and SOCE activity in VSMC. The results uncover a miRNA/SOCE regulatory circuit that orchestrates Ca2+ -dependent VSMC signaling during vascular remodeling and may serve as a potential therapeutic target pathway in occlusive vascular disease.

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Martin-Bornez, M., Dominguez-Liste, B., Avila-Medina, J., de Rojas-de Pedro, E. S., Galeano-Otero, I., Sanchez-Collado, J., Ordonez-Fernandez, A., Rosado, J. A., Hmadcha, A., Falcon, D., Smani, T.. 2026-01-23. miR-18a-5p upregulates Orai1 expression to promote vascular smooth muscle cell proliferation and neointimal hyperplasia after injury.. https://doi.org/10.64898/2026.01.20.700592

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