{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:32:55Z","timestamp":1791999175799,"version":"4.4.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>The blood\u2013brain barrier (BBB) is a highly specialized neurovascular unit that protects the brain from potentially harmful substances. In addition, the BBB also engages in the exchange of essential nutrients between the vasculature and brain parenchyma, which is critical for brain homeostasis. Brain diseases, including neurological disorders and cerebrovascular diseases, are often associated with disrupted BBB integrity, evidenced by increased permeability. Therefore, defining the mechanisms underlying the regulation of BBB integrity is crucial for the development of novel therapeutics targeting brain diseases. MicroRNAs (miRNA), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity. Here we review recent developments related to the role of miRNAs in regulating BBB integrity.<\/jats:p>","DOI":"10.3389\/fbioe.2021.673415","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T08:46:24Z","timestamp":1623401184000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Targeting microRNAs to Regulate the Integrity of the Blood\u2013Brain Barrier"],"prefix":"10.3389","volume":"9","author":[{"given":"Juntao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yankun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/0006-8993(87)90236-8","article-title":"Transcytosis at the blood-brain barrier.","volume":"57","author":"Ayloo","year":"2019","journal-title":"Curr. Opin. Neurobiol."},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1038\/srep35642","article-title":"Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse.","volume":"6","author":"Bai","year":"2016","journal-title":"Sci. Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nrd.2015.21","article-title":"From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery.","volume":"15","author":"Banks","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"B4","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nature13324","article-title":"Mfsd2a is critical for the formation and function of the blood-brain barrier.","volume":"509","author":"Ben-Zvi","year":"2014","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.omtn.2019.12.024","article-title":"MicroRNAs: possible regulatory molecular switch controlling the BBB microenvironment.","volume":"19","author":"Chakraborty","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"B6","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1073\/pnas.1209362110","article-title":"Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications.","volume":"110","author":"Cristante","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B7","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1093\/cvr\/cvx032","article-title":"Shear stress-regulated miR-27b controls pericyte recruitment by repressing SEMA6A and SEMA6D.","volume":"113","author":"Demolli","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1096\/fj.201500126","article-title":"MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats.","volume":"30","author":"Fang","year":"2016","journal-title":"FASEB J."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00866","article-title":"MicroRNA-126-3p attenuates intracerebral hemorrhage-induced blood-brain barrier disruption by regulating VCAM-1 expression.","volume":"13","author":"Fu","year":"2019","journal-title":"Front. Neurosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.brainres.2016.07.015","article-title":"miR-21-5p alleviates leakage of injured brain microvascular endothelial barrier in vitro through suppressing inflammation and apoptosis.","volume":"1650","author":"Ge","year":"2016","journal-title":"Brain Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41580-018-0045-7","article-title":"Regulation of microRNA function in animals.","volume":"20","author":"Gebert","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1038\/s41398-020-01054-3","article-title":"Blood-brain barrier associated tight junction disruption is a hallmark feature of major psychiatric disorders.","volume":"10","author":"Greene","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-13812-z","article-title":"Dual microglia effects on blood brain barrier permeability induced by systemic inflammation.","volume":"10","author":"Haruwaka","year":"2019","journal-title":"Nat. Commun."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2019.101664","article-title":"microRNA dysregulation in neurodegenerative diseases: a systematic review.","volume":"182","author":"Juzwik","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"B15","doi-asserted-by":"crossref","first-page":"D155","DOI":"10.1093\/nar\/gky1141","article-title":"miRBase: from microRNA sequences to function.","volume":"47","author":"Kozomara","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a029322","article-title":"Vascular endothelial (VE)-cadherin, endothelial adherens junctions, and vascular disease.","volume":"10","author":"Lampugnani","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.jconrel.2019.10.007","article-title":"MicroRNA delivery through nanoparticles.","volume":"313","author":"Lee","year":"2019","journal-title":"J. Control. Release"},{"key":"B18","doi-asserted-by":"crossref","first-page":"E2365","DOI":"10.1073\/pnas.1613233114","article-title":"miR-285-Yki\/Mask double-negative feedback loop mediates blood-brain barrier integrity in Drosophila.","volume":"114","author":"Li","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000734","article-title":"Targeting miR-27a\/VE-cadherin interactions rescues cerebral cavernous malformations in mice.","volume":"18","author":"Li","year":"2020","journal-title":"PLoS Biol."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2016.62","article-title":"The Poly-cistronic miR-23-27-24 complexes target endothelial cell junctions: differential functional and molecular effects of miR-23a and miR-23b.","volume":"5","author":"Li","year":"2016","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.2174\/1570159x16666180222164809","article-title":"The role of VE-cadherin in blood-brain barrier integrity under central nervous system pathological conditions.","volume":"16","author":"Li","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.yexcr.2016.03.026","article-title":"MicroRNA-107 prevents amyloid-beta induced blood-brain barrier disruption and endothelial cell dysfunction by targeting Endophilin-1.","volume":"343","author":"Liu","year":"2016","journal-title":"Exp. Cell Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.brainres.2014.05.022","article-title":"Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1\/2 pathway.","volume":"1573","author":"Liu","year":"2014","journal-title":"Brain Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1096\/fj.13-248880","article-title":"MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.","volume":"28","author":"Lopez-Ramirez","year":"2014","journal-title":"FASEB J."},{"key":"B25","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.gpb.2019.09.004","article-title":"Machine learning to detect Alzheimer\u2019s disease from circulating non-coding RNAs.","volume":"17","author":"Ludwig","year":"2019","journal-title":"Genomics Proteomics Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aay5686","article-title":"Endothelium-targeted deletion of the miR-15a\/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke.","volume":"13","author":"Ma","year":"2020","journal-title":"Sci. Signal."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18071356","article-title":"MicroRNA-210 suppresses junction proteins and disrupts blood-brain barrier integrity in neonatal rat hypoxic-ischemic brain injury.","volume":"18","author":"Ma","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3405","DOI":"10.1073\/pnas.1912012117","article-title":"Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier.","volume":"117","author":"Marcos-Contreras","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B29","doi-asserted-by":"publisher","first-page":"5992","DOI":"10.1523\/jneurosci.4796-12.2013","article-title":"HIV-1 Tat C modulates expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells.","volume":"33","author":"Mishra","year":"2013","journal-title":"J. Neurosci."},{"key":"B30","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering precision nanoparticles for drug delivery.","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B31","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1007\/s004010050355","article-title":"Role of the endothelial cytoskeleton in blood-brain-barrier permeability to protein.","volume":"90","author":"Nag","year":"1995","journal-title":"Acta Neuropathol."},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-05065-z","article-title":"miR-103 promotes endothelial maladaptation by targeting lncWDR59.","volume":"9","author":"Natarelli","year":"2018","journal-title":"Nat. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41591-018-0297-y","article-title":"Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.","volume":"25","author":"Nation","year":"2019","journal-title":"Nat. Med."},{"key":"B34","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20190062","article-title":"The blood-brain barrier in health and disease: important unanswered questions.","volume":"217","author":"Profaci","year":"2020","journal-title":"J. Exp. Med."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113382","article-title":"Emerging role of microRNAs in ischemic stroke with comorbidities.","volume":"331","author":"Qian","year":"2020","journal-title":"Exp. Neurol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1523\/jneurosci.3965-12.2013","article-title":"MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis.","volume":"33","author":"Reijerkerk","year":"2013","journal-title":"J. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1038\/jcbfm.2015.154","article-title":"miR-98 and let-7g\u2217 protect the blood-brain barrier under neuroinflammatory conditions.","volume":"35","author":"Rom","year":"2015","journal-title":"J. Cereb Blood Flow Metab."},{"key":"B38","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nrd.2016.246","article-title":"MicroRNA therapeutics: towards a new era for the management of cancer and other diseases.","volume":"16","author":"Rupaimoole","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"B39","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1007\/3-211-30714-1_29","article-title":"Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats.","volume":"96","author":"Shigemori","year":"2006","journal-title":"Acta Neurochir. Suppl."},{"key":"B40","doi-asserted-by":"crossref","DOI":"10.1038\/s41426-018-0157-3","article-title":"miR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9.","volume":"7","author":"Song","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"B41","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-017-00813-z","article-title":"MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology.","volume":"8","author":"Sonneville","year":"2017","journal-title":"Nat. Commun."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1161\/strokeaha.118.023648","article-title":"Serum MicroRNA-based risk prediction for stroke.","volume":"50","author":"Sonoda","year":"2019","journal-title":"Stroke"},{"key":"B43","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1002\/mds.27542","article-title":"The biomarker potential of cell-free microRNA from cerebrospinal fluid in Parkinsonian Syndromes.","volume":"34","author":"Starhof","year":"2019","journal-title":"Mov. Disord."},{"key":"B44","doi-asserted-by":"publisher","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":"B45","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1038\/s41593-018-0234-x","article-title":"The role of brain vasculature in neurodegenerative disorders.","volume":"21","author":"Sweeney","year":"2018","journal-title":"Nat. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/ncb1752","article-title":"Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5.","volume":"10","author":"Taddei","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1007\/s00125-018-4770-4","article-title":"Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models.","volume":"62","author":"Ting","year":"2019","journal-title":"Diabetologia"},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms7716","article-title":"Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier.","volume":"6","author":"Tominaga","year":"2015","journal-title":"Nat. Commun."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1161\/atvbaha.118.310822","article-title":"MicroRNA-mediated therapy modulating blood-brain barrier disruption improves vascular cognitive impairment.","volume":"38","author":"Toyama","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41580-018-0059-1","article-title":"Regulation of microRNA biogenesis and its crosstalk with other cellular pathways.","volume":"20","author":"Treiber","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00056","article-title":"Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke.","volume":"10","author":"Turner","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nature25739","article-title":"A molecular atlas of cell types and zonation in the brain vasculature.","volume":"554","author":"Vanlandewijck","year":"2018","journal-title":"Nature"},{"key":"B53","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1177\/0271678x20926787","article-title":"MicroRNA-30a regulates acute cerebral ischemia-induced blood-brain barrier damage through ZnT4\/zinc pathway.","volume":"41","author":"Wang","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"B54","doi-asserted-by":"publisher","first-page":"20041","DOI":"10.1074\/jbc.ra118.001858","article-title":"miR-27a-3p protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by targeting endothelial aquaporin-11.","volume":"293","author":"Xi","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1038\/cr.2017.62","article-title":"Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity.","volume":"27","author":"Xu","year":"2017","journal-title":"Cell Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1182\/blood-2012-12-473017","article-title":"Regulation of vascular leak and recovery from ischemic injury by general and VE-cadherin-restricted miRNA antagonists of miR-27.","volume":"122","author":"Young","year":"2013","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","first-page":"13762","DOI":"10.1096\/fj.201903092r","article-title":"MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR\/FOXO1 pathway in cerebral ischemia.","volume":"34","author":"Zhang","year":"2020","journal-title":"FASEB J."},{"key":"B58","doi-asserted-by":"publisher","first-page":"4434","DOI":"10.1158\/0008-5472.can-16-3129","article-title":"Targeting vascular endothelial-cadherin in tumor-associated blood vessels promotes T cell-mediated immunotherapy.","volume":"77","author":"Zhao","year":"2017","journal-title":"Cancer Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.expneurol.2019.03.017","article-title":"MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice.","volume":"316","author":"Zuo","year":"2019","journal-title":"Exp. Neurol."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2021.673415\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T08:46:38Z","timestamp":1623401198000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2021.673415\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,11]]},"references-count":59,"alternative-id":["10.3389\/fbioe.2021.673415"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2021.673415","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,11]]},"article-number":"673415"}}