{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:59:23Z","timestamp":1783400363930,"version":"3.54.6"},"reference-count":55,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["2R01AA023610"],"award-info":[{"award-number":["2R01AA023610"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Light alcohol consumption (LAC) may reduce the incidence and improve the prognosis of ischemic stroke. Recently, we found that LAC promotes cerebral angiogenesis and inhibits early inflammation following ischemic stroke. In addition, LAC upregulates lipocalin-type prostaglandin D2 synthase (L-PGDS) in the brain. Thus, we determined the role of endothelial L-PGDS in the protective effect of LAC. In in vitro studies, chronic exposure to low-concentration ethanol upregulated L-PGDS and significantly increased the proliferation in cultured C57BL\/6J mouse brain microvascular endothelial cells (MBMVECs). AT-56, a selective L-PGDS inhibitor, abolished low-concentration ethanol exposure-induced proliferation. In in vivo studies, 8-week gavage feeding with 0.7 g\/kg\/day ethanol, defined as LAC, promoted cerebral angiogenesis under physiological conditions and following ischemic stroke in male C57BL\/6J mice. In addition, LAC inhibited the post-ischemic expression of adhesion molecules, neutrophil infiltration, and microglial activation. AT-56 and endothelial cell (EC)-specific L-PGDS conditional knockout did not significantly alter cerebral angiogenesis and post-ischemic inflammation in the control mice but eliminated the pro-angiogenic and anti-inflammatory effects of LAC. Furthermore, EC-specific L-PGDS conditional knockout alleviated the neuroprotective effect of LAC against cerebral ischemia\/reperfusion injury. These findings suggest that endothelial L-PGDS may be crucial in the pro-angiogenic and anti-inflammatory effects of LAC against ischemic stroke.<\/jats:p>","DOI":"10.3390\/cells13232007","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T04:13:03Z","timestamp":1733371983000},"page":"2007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Endothelial L-PGDS in the Pro-Angiogenic and Anti-Inflammatory Effects of Low-Dose Alcohol Consumption"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7717-0804","authenticated-orcid":false,"given":"Jiyu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3223-9716","authenticated-orcid":false,"given":"Utsab","family":"Subedi","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5121-735X","authenticated-orcid":false,"given":"Pushpa","family":"Subedi","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-8948","authenticated-orcid":false,"given":"Manikandan","family":"Panchatcharam","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, LSU Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"ref_1","first-page":"1382","article-title":"Reperfusion injury after focal cerebral ischemia: The role of inflammation and the therapeutic horizon","volume":"43","author":"Jean","year":"1998","journal-title":"Neurosurgery"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature10144","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1159\/000444810","article-title":"MLC901 Favors Angiogenesis and Associated Recovery after Ischemic Stroke in Mice","volume":"42","author":"Gandin","year":"2016","journal-title":"Cerebrovasc. Dis."},{"key":"ref_4","first-page":"203","article-title":"Some remarks on the growth-rate and angiogenesis of microvessels in ischemic stroke. Morphometric and immunocytochemical studies","volume":"44","author":"Krupinski","year":"1993","journal-title":"Patol. Pol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1161\/STROKEAHA.111.642710","article-title":"Angiogenesis: A harmonized target for recovery after stroke","volume":"43","author":"Ergul","year":"2012","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Seto, S.W., Chang, D., Jenkins, A., Bensoussan, A., and Kiat, H. (2016). Angiogenesis in Ischemic Stroke and Angiogenic Effects of Chinese Herbal Medicine. J. Clin. Med., 5.","DOI":"10.3390\/jcm5060056"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1172\/JCI200317977","article-title":"VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia","volume":"111","author":"Sun","year":"2003","journal-title":"J. Clin. Invest."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, J., Li, C., Loreno, E.G., Miriyala, S., Panchatcharam, M., Lu, X., and Sun, H. (2021). Chronic Low-Dose Alcohol Consumption Promotes Cerebral Angiogenesis in Mice. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.681627"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","article-title":"Cell biology of ischemia\/reperfusion injury","volume":"298","author":"Kalogeris","year":"2012","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/1742-2094-10-115","article-title":"Leukocyte infiltration in experimental stroke","volume":"10","author":"Gronberg","year":"2013","journal-title":"J. Neuroinflamm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1161\/STROKEAHA.115.010620","article-title":"Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice","volume":"46","author":"Herz","year":"2015","journal-title":"Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12974-016-0774-5","article-title":"Cerebral ischemic damage in diabetes: An inflammatory perspective","volume":"14","author":"Shukla","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xu, G., Li, C., Parsiola, A.L., Li, J., McCarter, K.D., Shi, R., Mayhan, W.G., and Sun, H. (2019). Dose-Dependent Influences of Ethanol on Ischemic Stroke: Role of Inflammation. Front. Cell Neurosci., 13.","DOI":"10.3389\/fncel.2019.00006"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1161\/01.RES.86.9.967","article-title":"Fluid shear stress induces lipocalin-type prostaglandin D(2) synthase expression in vascular endothelial cells","volume":"86","author":"Taba","year":"2000","journal-title":"Circ. Res."},{"key":"ref_15","unstructured":"Urade, Y., Eguchi, N., and Hayaishi, O. (2013). Lipocalin-type prostaglandin D synthase as an enzymic lipocalin. Madame Curie Bioscience Database, Landes Bioscience."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.neuroscience.2009.02.039","article-title":"Lipocalin-prostaglandin D synthase is a critical beneficial factor in transient and permanent focal cerebral ischemia","volume":"160","author":"Saleem","year":"2009","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Li, C., Li, J., Loreno, E.G., Miriyala, S., Panchatcharam, M., and Sun, H. (2021). Protective Effect of Low-Dose Alcohol Consumption against Post-Ischemic Neuronal Apoptosis: Role of L-PGDS. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010133"},{"key":"ref_18","first-page":"304","article-title":"Endogenous prostaglandin D2 synthesis inhibits e-selectin generation in human umbilical vein endothelial cells","volume":"3","author":"Negoro","year":"2011","journal-title":"Sci. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100439","DOI":"10.1016\/j.jlr.2023.100439","article-title":"Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis","volume":"64","author":"Horikami","year":"2023","journal-title":"J. Lipid Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Vidal-Itriago, A., Radford, R.A.W., Aramideh, J.A., Maurel, C., Scherer, N.M., Don, E.K., Lee, A., Chung, R.S., Graeber, M.B., and Morsch, M. (2022). Microglia morphophysiological diversity and its implications for the CNS. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.997786"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"705","DOI":"10.4103\/1673-5374.322423","article-title":"Microglia regulation of synaptic plasticity and learning and memory","volume":"17","author":"Cornell","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, C., Li, J., Loreno, E.G., Miriyala, S., Panchatcharam, M., Lu, X., and Sun, H. (2021). Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARgamma in Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105121"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, C., Li, J.Y., Xu, G.D., and Sun, H. (2020). Influence of Chronic Ethanol Consumption on Apoptosis and Autophagy Following Transient Focal Cerebral Ischemia in Male Mice. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-63213-2"},{"key":"ref_24","first-page":"300","article-title":"Calculation of blood alcohol concentration (BAC) by sex, weight, number of drinks and time","volume":"78","author":"Fisher","year":"1987","journal-title":"Can. J. Public. Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.brainres.2007.11.061","article-title":"Effect of chronic alcohol consumption on brain damage following transient focal ischemia","volume":"1194","author":"Sun","year":"2008","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1111\/j.1530-0277.1998.tb03692.x","article-title":"How do physicians define \u201clight\u201d, \u201cmoderate\u201d, and \u201cheavy\u201d drinking?","volume":"22","author":"Abel","year":"1998","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_27","first-page":"2575","article-title":"Molecular mechanisms of sleep-wake regulation: Roles of prostaglandins D2 and E2","volume":"5","author":"Hayaishi","year":"1991","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1006\/bbrc.1994.2297","article-title":"Identification of beta-trace as prostaglandin D synthase","volume":"203","author":"Watanabe","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/1096-9861(20001204)428:1<62::AID-CNE6>3.0.CO;2-E","article-title":"Cellular localization of lipocalin-type prostaglandin D synthase (beta-trace) in the central nervous system of the adult rat","volume":"428","author":"Beuckmann","year":"2000","journal-title":"J. Comp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.1523\/JNEUROSCI.22-12-04885.2002","article-title":"Perineuronal oligodendrocytes protect against neuronal apoptosis through the production of lipocalin-type prostaglandin D synthase in a genetic demyelinating model","volume":"22","author":"Taniike","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1471-4159.2006.03753.x","article-title":"Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides","volume":"97","author":"Mohri","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gonzalez-Rodriguez, P.J., Li, Y., Martinez, F., and Zhang, L.B. (2014). Dexamethasone Protects Neonatal Hypoxic-Ischemic Brain Injury via L-PGDS-Dependent PGD(2)-DP1-pERK Signaling Pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114470"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/bph.12103","article-title":"Prostaglandin E(2)-induced intercellular adhesion molecule-1 expression is mediated by cAMP\/Epac signalling modules in bEnd.3 brain endothelial cells","volume":"169","author":"Park","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1021\/acsptsci.0c00040","article-title":"Inhibiting the PGE(2) Receptor EP2 Mitigates Excitotoxicity and Ischemic Injury","volume":"3","author":"Li","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40035-023-00366-w","article-title":"Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis","volume":"12","author":"Nango","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1136\/svn-2018-000196","article-title":"Microglial activation after ischaemic stroke","volume":"4","author":"Zhang","year":"2019","journal-title":"Stroke Vasc. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1172\/JCI31450","article-title":"Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology","volume":"117","author":"Shaftel","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.4049\/jimmunol.171.8.3936","article-title":"Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1","volume":"171","author":"Hammad","year":"2003","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1161\/01.RES.82.2.204","article-title":"Prostaglandin D2 inhibits inducible nitric oxide synthase expression in rat vascular smooth muscle cells","volume":"82","author":"Nagoshi","year":"1998","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1097\/00004872-200207000-00021","article-title":"Endogenous prostaglandin D2 synthesis reduces an increase in plasminogen activator inhibitor-1 following interleukin stimulation in bovine endothelial cells","volume":"20","author":"Negoro","year":"2002","journal-title":"J. Hypertens."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.imlet.2005.10.004","article-title":"Positioning prostanoids of the D and J series in the immunopathogenic scheme","volume":"102","author":"Herlong","year":"2006","journal-title":"Immunol. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Sun, H., Xiong, W., Arrick, D.M., and Mayhan, W.G. (2012). Low-dose alcohol consumption protects against transient focal cerebral ischemia in mice: Possible role of PPARgamma. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041716"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1097\/01.jnen.0000178852.83680.3c","article-title":"The nonthiazolidinedione PPARgamma agonist L-796,449 is neuroprotective in experimental stroke","volume":"64","author":"Pereira","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.neuroscience.2004.10.021","article-title":"Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia","volume":"130","author":"Sundararajan","year":"2005","journal-title":"Neuroscience"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1096\/fj.03-0246fje","article-title":"Genetic loci that control vascular endothelial growth factor-induced angiogenesis","volume":"17","author":"Rogers","year":"2003","journal-title":"FASEB J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/path.4993","article-title":"Lipocalin-type prostaglandin D synthase-derived PGD(2) attenuates malignant properties of tumor endothelial cells","volume":"244","author":"Omori","year":"2018","journal-title":"J. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"24778","DOI":"10.18632\/aging.202367","article-title":"L-PGDS deficiency accelerated the development of naturally occurring age-related osteoarthritis","volume":"12","author":"Ouhaddi","year":"2020","journal-title":"Aging"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20009","DOI":"10.1073\/pnas.0805171105","article-title":"Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo","volume":"105","author":"Murata","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","first-page":"693","article-title":"Loss of PPAR gamma in endothelial cells leads to impaired angiogenesis","volume":"129","author":"Akinrinade","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.cardiores.2007.01.010","article-title":"PPAR-gamma agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts","volume":"74","author":"Chintalgattu","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.mce.2015.02.012","article-title":"Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPAR gamma mediated pathways in 3T3-L1 adipocytes","volume":"406","author":"Hasan","year":"2015","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.brainres.2006.03.114","article-title":"Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia","volume":"1093","author":"Chu","year":"2006","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1161\/CIRCRESAHA.110.235390","article-title":"Early atheroma-derived agonists of peroxisome proliferator-activated receptor-gamma trigger intramedial angiogenesis in a smooth muscle cell-dependent manner","volume":"109","author":"Gomez","year":"2011","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/01.WCB.0000041283.53351.CB","article-title":"Temporal profile of angiogenesis and expression of related genes in the brain after ischemia","volume":"23","author":"Hayashi","year":"2003","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/s41401-023-01061-2","article-title":"Angiogenesis after ischemic stroke","volume":"44","author":"Fang","year":"2023","journal-title":"Acta Pharmacol. Sin."}],"updated-by":[{"DOI":"10.3390\/cells15010064","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000}}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/23\/2007\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:46:30Z","timestamp":1767192390000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/23\/2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,5]]},"references-count":55,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["cells13232007"],"URL":"https:\/\/doi.org\/10.3390\/cells13232007","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,5]]}}}