{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:17:09Z","timestamp":1784265429103,"version":"3.55.0"},"reference-count":28,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Louisiana State University Health Shreveport Chancellor\u2019s Aim High Research Award"},{"name":"the National Institute on Drug Abuse Drug Supply Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>Background\/Objectives: Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood\u2013brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated the effects of METH on syndecan-1 expression and endothelial function in primary rat retinal microvascular endothelial cells (RRMECs) and isolated ophthalmic arteries. Methods: We assessed METH-induced changes in mRNA and protein expression levels of syndecan-1, matrix metalloproteinase (MMP)-2, and MMP-9. Endothelial function was evaluated using scratch migration assays and trans-endothelial electrical resistance (TEER) measurements. The mechanistic involvement of MMP-9 and trace amine-associated receptor 1 (TAAR-1), a known receptor for METH, was examined using selective pharmacological inhibitors. Results: METH exposure significantly decreased syndecan-1 expression and increased MMP-9 levels. These changes were accompanied by impaired endothelial migration and reduced TEER in RRMECs. Similar findings were confirmed in cultured ophthalmic arteries, reinforcing the translational relevance of our in vitro results. Inhibition of MMPs restored syndecan-1 expression and rescued endothelial function. Furthermore, TAAR-1 antagonism protected against syndecan-1 degradation, reduced MMP-9 upregulation, and improved endothelial migration and barrier resistance. Conclusions: Our findings suggest that METH induces loss of syndecan-1 and retinal vascular integrity by promoting TAAR-1\u2013mediated MMP-9 upregulation. Targeting the TAAR-1\/MMP-9 axis may offer a promising therapeutic strategy for preventing METH-induced microvascular damage in the retina.<\/jats:p>","DOI":"10.3390\/pathophysiology32030041","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T10:35:17Z","timestamp":1756204517000},"page":"41","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Methamphetamine-Induced Loss of Syndecan-1 and Retinal Endothelial Integrity via the TAAR-1\/MMP-9 Pathway"],"prefix":"10.3390","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-5366","authenticated-orcid":false,"given":"Minsup","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taekyung","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5656-0169","authenticated-orcid":false,"given":"Ivan A.","family":"Alvarez","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA"},{"name":"Current: Department of Otolaryngology-Head and Neck Surgery, University of Kentucky College of Medicine, 740 S. Limestone Street, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Leskova","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7334-8153","authenticated-orcid":false,"given":"Norman R.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1161\/ATVBAHA.119.312461","article-title":"Methamphetamine Use and Cardiovascular Disease","volume":"39","author":"Kevil","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107964","DOI":"10.1016\/j.exer.2020.107964","article-title":"Acute changes in the retina and central retinal artery with methamphetamine","volume":"193","author":"Lee","year":"2020","journal-title":"Exp. Eye. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.brainres.2011.07.013","article-title":"Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: Role of tight junction proteins and matrix metalloproteinase-9","volume":"1411","author":"Martins","year":"2011","journal-title":"Brain Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1038\/jcbfm.2009.112","article-title":"Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells","volume":"29","author":"Ramirez","year":"2009","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sanches, E.S., Boia, R., Leitao, R.A., Madeira, M.H., Fontes-Ribeiro, C.A., Ambrosio, A.F., Fernandes, R., and Silva, A.P. (2023). Attention-Deficit\/Hyperactivity Disorder Animal Model Presents Retinal Alterations and Methylphenidate Has a Differential Effect in ADHD versus Control Conditions. Antioxidants, 12.","DOI":"10.3390\/antiox12040937"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e14319","DOI":"10.1111\/eci.14319","article-title":"Neurovascular dysfunction in psychiatric disorders: Underlying mechanisms and therapeutic approaches","volume":"55","author":"Sanches","year":"2025","journal-title":"Eur. J. Clin. Invest."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.brainres.2010.12.017","article-title":"Methamphetamine causes sustained depression in cerebral blood flow","volume":"1373","author":"Polesskaya","year":"2011","journal-title":"Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102362","DOI":"10.1016\/j.arr.2024.102362","article-title":"Focus of endothelial glycocalyx dysfunction in ischemic stroke and Alzheimer\u2019s disease: Possible intervention strategies","volume":"99","author":"Balistreri","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18614","DOI":"10.1074\/jbc.RA120.015105","article-title":"Ischemic stroke disrupts the endothelial glycocalyx through activation of proHPSE via acrolein exposure","volume":"295","author":"Ko","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1136\/jnnp-2017-316071","article-title":"Stroke and methamphetamine use in young adults: A review","volume":"88","author":"Lappin","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.matbio.2011.10.001","article-title":"Molecular functions of syndecan-1 in disease","volume":"31","author":"Teng","year":"2012","journal-title":"Matrix Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3390\/pathophysiology31010007","article-title":"High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothel. Cells and in Isolated Ophthalmic Arteries","volume":"31","author":"Alvarez","year":"2024","journal-title":"Pathophysiology"},{"key":"ref_13","first-page":"1135","article-title":"Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature","volume":"43","author":"Gotte","year":"2002","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00424-007-0212-8","article-title":"The endothelial glycocalyx: Composition, functions, and visualization","volume":"454","author":"Reitsma","year":"2007","journal-title":"Pflug. Arch."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.matbio.2013.10.005","article-title":"Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse","volume":"35","author":"Ramani","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.2147\/JIR.S331020","article-title":"Syndecan-1 Shedding by Matrix Metalloproteinase-9 Signaling Regulates Alveolar Epithelial Tight Junction in Lipopolysaccharide-Induced Early Acute Lung Injury","volume":"14","author":"Zhang","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.ajpath.2019.11.015","article-title":"The Pathological Relevance of Increased Endothelial Glycocalyx Permeability","volume":"190","author":"Butler","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.exer.2018.11.012","article-title":"Effect of diabetes and hyaluronidase on the retinal endothelial glycocalyx in mice","volume":"179","author":"Leskova","year":"2019","journal-title":"Exp. Eye. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109617","DOI":"10.1016\/j.exer.2023.109617","article-title":"Decreased retinal and choroidal endothelial surface molecules in spontaneously hypertensive rats","volume":"234","author":"Eshaq","year":"2023","journal-title":"Exp. Eye. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1111\/febs.12134","article-title":"Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between alphaVbeta3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis","volume":"280","author":"Rapraeger","year":"2013","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fnins.2015.00039","article-title":"The trace amine-associated receptor 1 modulates methamphetamine\u2019s neurochemical and behavioral effects","volume":"9","author":"Cotter","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1124\/jpet.115.229765","article-title":"In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1","volume":"357","author":"Simmler","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1167\/iovs.66.9.8","article-title":"Retinal Angiogenesis in Methamphetamine Self-Administration Rats","volume":"66","author":"Lee","year":"2025","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108540","DOI":"10.1016\/j.exer.2021.108540","article-title":"Retinal hypoxia and angiogenesis with methamphetamine","volume":"206","author":"Lee","year":"2021","journal-title":"Exp. Eye. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"127170","DOI":"10.1155\/2013\/127170","article-title":"Angiogenesis and its therapeutic opportunities","volume":"2013","author":"Yoo","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.preteyeres.2003.08.001","article-title":"Retinal and choroidal angiogenesis: Pathophysiology and strategies for inhibition","volume":"22","author":"Das","year":"2003","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/syn.20365","article-title":"Methamphetamine blood concentrations in human abusers: Application to pharmacokinetic modeling","volume":"61","author":"Melega","year":"2007","journal-title":"Synapse"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1111\/febs.12174","article-title":"Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains","volume":"280","author":"Multhaupt","year":"2013","journal-title":"FEBS J."}],"container-title":["Pathophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1873-149X\/32\/3\/41\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:50Z","timestamp":1760034770000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1873-149X\/32\/3\/41"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":28,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["pathophysiology32030041"],"URL":"https:\/\/doi.org\/10.3390\/pathophysiology32030041","relation":{},"ISSN":["1873-149X"],"issn-type":[{"value":"1873-149X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]}}}