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After an ischemia event, RA reduces the effects of blood\u2013brain barrier disruption by blocking the apoptotic signaling pathway. However, the effect of RA on smooth muscle cells (SMCs), which are crucial to maintaining blood perfusion, has never been investigated. This study aimed to evaluate the effect of RA on the vasoactive response of middle cerebral artery SMCs in normal and ischemic contexts (O2 and glucose deprivation, OGD). For this purpose, SMCs cultures were incubated with RA, and the vasoactive response was evaluated in both conditions (OGD and non-OGD). To simulate OGD, co-cultures of neurons and astrocytes were made and incubated with RA to analyze the effect of the secretome released by these cells on SMCs contractility. In non-OGD conditions, RA induced rapid relaxation of SMCs and, in the long term (24 h), promoted cell contraction. In OGD conditions, SMCs contractility patterns were different when pre-incubated with RA. In these conditions, NA loses its contractility effect, and SNP seems to revert its relaxant effect. However, SMCs pre-incubated with 5 uM RA show the vasorelaxant pattern typical of SNP, despite the OGD condition. These effects demonstrate an effect of RA on the vasoactive profile of SMCs, with therapeutic potential in OGD conditions.<\/jats:p>","DOI":"10.3390\/jox15030069","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T03:59:26Z","timestamp":1747108766000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of Retinoic Acid on the Cerebral Vasculature: Analysis of the Vasoactive Response of Smooth Muscle Cells in Normal and Ischemic Contexts"],"prefix":"10.3390","volume":"15","author":[{"given":"Manuel R.","family":"Pouso","sequence":"first","affiliation":[{"name":"Health Sciences Research Centre (CICS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilha, Portugal"},{"name":"Faculty of Health Sciences (FCS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1728-2855","authenticated-orcid":false,"given":"Emanuel","family":"Farinha","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"Faculty of Health Sciences (FCS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5358-9889","authenticated-orcid":false,"given":"Henrique E.","family":"Costa","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilha, Portugal"},{"name":"Faculty of Health Sciences (FCS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4752-6398","authenticated-orcid":false,"given":"Margarida","family":"Lorigo","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilha, Portugal"},{"name":"Faculty of Health Sciences (FCS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"Cloud Computing Competence Centre, University of Beira Interior (UBI), 6200-501 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7942-0432","authenticated-orcid":false,"given":"Gra\u00e7a","family":"Baltazar","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilha, Portugal"},{"name":"Faculty of Health Sciences (FCS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4823-5701","authenticated-orcid":false,"given":"Elisa","family":"Cairrao","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilha, Portugal"},{"name":"Faculty of Health Sciences (FCS), University of Beira Interior (UBI), 6200-506 Covilha, Portugal"},{"name":"Cloud Computing Competence Centre, University of Beira Interior (UBI), 6200-501 Covilha, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1111\/apha.12250","article-title":"The neurovascular unit\u2014Concept review","volume":"210","author":"Muoio","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.tins.2013.07.001","article-title":"Sugar for the brain: The role of glucose in physiological and pathological brain function","volume":"36","author":"Mergenthaler","year":"2013","journal-title":"Trends Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.neuron.2017.07.030","article-title":"The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease","volume":"96","author":"Iadecola","year":"2017","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nn.4288","article-title":"Pericytes of the neurovascular unit: Key functions and signaling pathways","volume":"19","author":"Sweeney","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yu, X., Ji, C., and Shao, A. (2020). Neurovascular Unit Dysfunction and Neurodegenerative Disorders. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00334"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1111\/febs.13412","article-title":"The dynamic blood-brain barrier","volume":"282","author":"Keaney","year":"2015","journal-title":"FEBS J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s12975-013-0306-x","article-title":"Smooth muscle cell phenotypic switching in stroke","volume":"5","author":"Poittevin","year":"2014","journal-title":"Transl. Stroke Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/BF03085963","article-title":"Regulation and characteristics of vascular smooth muscle cell phenotypic diversity","volume":"15","author":"Rensen","year":"2007","journal-title":"Neth. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.12997\/jla.2020.9.1.124","article-title":"Canonical Transient Receptor Potential Channels and Vascular Smooth Muscle Cell Plasticity","volume":"9","author":"Nishida","year":"2020","journal-title":"J. Lipid Atheroscler"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"502","DOI":"10.2174\/1567202616666191026122642","article-title":"The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells","volume":"16","author":"Quelhas","year":"2019","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kuriakose, D., and Xiao, Z. (2020). Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207609"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.ncl.2008.07.003","article-title":"Epidemiology of ischemic and hemorrhagic stroke: Incidence, prevalence, mortality, and risk factors","volume":"26","author":"Grysiewicz","year":"2008","journal-title":"Neurol. Clin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1007\/s10571-021-01103-5","article-title":"In Vitro Model for Ischemic Stroke: Functional Analysis of Vascular Smooth Muscle Cells","volume":"42","author":"Mariana","year":"2021","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e350","DOI":"10.1002\/term.2427","article-title":"Challenging the great vascular wall: Can we envision a simple yet comprehensive therapy for stroke?","volume":"12","author":"Santos","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1007\/s10571-017-0483-3","article-title":"Impact of Astrocytes on the Injury Induced by In Vitro Ischemia","volume":"37","author":"Roque","year":"2017","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1111\/j.1471-4159.2010.06867.x","article-title":"Inflammatory chemokine release of astrocytes in vitro is reduced by all-trans retinoic acid","volume":"114","author":"Regen","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1471-4159.2008.05395.x","article-title":"Anti-inflammatory effect of retinoic acid on prostaglandin synthesis in cultured cortical astrocytes","volume":"106","author":"Kampmann","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"164","DOI":"10.2174\/187152411796011303","article-title":"Astrocytes: Targets for neuroprotection in stroke","volume":"11","author":"Barreto","year":"2011","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.neuint.2011.11.009","article-title":"Reactive oxygen species and ischemic cerebrovascular disease","volume":"60","author":"Olmez","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ceca.2018.02.001","article-title":"Retinoic acid inhibits neuronal voltage-gated calcium channels","volume":"72","author":"Lukewich","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.brainresbull.2022.03.011","article-title":"Effect of retinoic acid on the neurovascular unit: A review","volume":"184","author":"Pouso","year":"2022","journal-title":"Brain Res. Bull."},{"key":"ref_22","first-page":"243","article-title":"Retinoid-xenobiotic interactions: The Ying and the Yang","volume":"4","author":"Shmarakov","year":"2015","journal-title":"Hepatobiliary Surg. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Powa\u0142a, K., \u017bo\u0142ek, T., Brown, G., and Kutner, A. (2024). Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor \u03b3. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126568"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.reprotox.2020.03.002","article-title":"Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: The European viewpoint","volume":"93","author":"Grignard","year":"2020","journal-title":"Reprod. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101400","DOI":"10.1016\/j.tice.2020.101400","article-title":"Characterization of culture from smooth muscle cells isolated from rat middle cerebral arteries","volume":"66","author":"Quelhas","year":"2020","journal-title":"Tissue Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00401-017-1667-0","article-title":"Ischemic stroke: Experimental models and reality","volume":"133","author":"Sommer","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"C135","DOI":"10.1152\/ajpcell.00136.2018","article-title":"Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke","volume":"316","author":"Yang","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"135979","DOI":"10.1016\/j.neulet.2021.135979","article-title":"Retinoic acid exerts neuroprotective effects against focal cerebral ischemia by preventing apoptotic cell death","volume":"757","author":"Kang","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s11626-008-9161-6","article-title":"Isolation and culture of human umbilical artery smooth muscle cells expressing functional calcium channels","volume":"45","author":"Alvarez","year":"2009","journal-title":"In Vitro Cell. Dev. Biol. Anim."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10463","DOI":"10.1021\/nn304541h","article-title":"Polymeric nanoparticles to control the differentiation of neural stem cells in the subventricular zone of the brain","volume":"6","author":"Santos","year":"2012","journal-title":"ACS Nano"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.brainres.2010.05.091","article-title":"Role of alpha-adrenoceptors and prostacyclin in the enhanced adrenergic reactivity of goat cerebral arteries after ischemia-reperfusion","volume":"1346","author":"Monge","year":"2010","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1111\/j.1476-5381.1994.tb17159.x","article-title":"Inhibition of nitric oxide synthesis in vascular smooth muscle by retinoids","volume":"113","author":"Hirokawa","year":"1994","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, J., Zhang, Y., Zhang, D., Wang, W., Xie, H., Ruan, J., Jin, Y., Li, T., Li, X., and Zhao, B. (2024). Ca2+ oscillation in vascular smooth muscle cells control myogenic spontaneous vasomotion and counteract post-ischemic no-reflow. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06010-1"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1093\/biolre\/ioaa122","article-title":"Retinoic acid receptor antagonists for male contraception: Current status\u2020","volume":"103","author":"Noman","year":"2020","journal-title":"Biol. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1042\/bj3230521","article-title":"Stimulation of mucin exocytosis from human epithelial cells by nitric oxide: Evidence for a cGMP-dependent and a cGMP-independent pathway","volume":"323","author":"Branka","year":"1997","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1021\/acs.molpharmaceut.2c00661","article-title":"Nitroprusside\u2014Expanding the Potential Use of an Old Drug Using Nanoparticles","volume":"20","author":"Paz","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2147\/CMAR.S32449","article-title":"Retinoids in the treatment of glioma: A new perspective","volume":"4","author":"Mawson","year":"2012","journal-title":"Cancer Manag. Res."}],"container-title":["Journal of Xenobiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4713\/15\/3\/69\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:30:42Z","timestamp":1760031042000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4713\/15\/3\/69"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,10]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["jox15030069"],"URL":"https:\/\/doi.org\/10.3390\/jox15030069","relation":{},"ISSN":["2039-4713"],"issn-type":[{"value":"2039-4713","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,10]]}}}