{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T17:58:43Z","timestamp":1772647123574,"version":"3.50.1"},"reference-count":94,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Drug Discovery Center Pilot","award":["E073601006"],"award-info":[{"award-number":["E073601006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Type 2 diabetes (T2D) features insulin resistance that promotes cerebrovascular injury, yet the immune signals linking metabolic stress to vascular dysfunction remain unclear. We tested the hypothesis that insulin resistance and soluble vascular cell adhesion molecule-1 (sVCAM1) act through complementary pathways in mast cells (MCs) to raise circulating histamine levels and impair cerebral vascular function. In a high-fat diet (HFD) plus low-dose streptozotocin (STZ) model, plasma histamine rose sharply after the onset of insulin resistance and remained elevated. Plasma sVCAM1 levels also increased after insulin resistance. In vitro, recombinant sVCAM1 upregulated histidine decarboxylase (HDC) in native MCs in a dose-dependent manner, indicating a shift toward histamine synthesis, but did not enhance degranulation. In contrast, pharmacological inhibition of Akt with MK2206 activated Glycogen Synthase Kinase 3 beta (GSK3\u03b2) and increased MC degranulation without affecting HDC expression. Diabetic endothelial cell monolayers exhibited a ~twofold reduction in transendothelial electrical resistance consistent with impaired blood\u2013brain barrier (BBB) integrity. Diabetic cerebral arteries showed receptor remodeling that favored constriction with histamine H1 receptor (H1R) expression increasing in vascular smooth muscle, while endothelial H1R and histamine H2 receptor (H2R) decreased. Functionally, insulin treatment lowered HOMA2-IR in T2D mice but did not restore cerebral artery myogenic tone or improve stroke outcomes after distal middle cerebral artery occlusion (dMCAO). Neutralizing VCAM1 with a monoclonal antibody reduced circulating sVCAM1 and histamine levels, and, together with the GSK3\u03b2 inhibitor Tideglusib, stabilized MCs, normalized cerebral artery tone, and reduced post-MCAO infarct size and edema. These findings identify two distinct yet complementary mast cell pathways in T2D, highlight an immune-vascular interface that drives cerebrovascular dysfunction, and propose sVCAM1 blockade plus GSK3\u03b2 inhibition as rational strategies to protect cerebral vascular function in the diabetic brain.<\/jats:p>","DOI":"10.3390\/cells15050455","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:01:07Z","timestamp":1772636467000},"page":"455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Soluble VCAM1 and GSK3\u03b2 Improves Cerebrovascular Function and Reduces Stroke Pathology in Diabetic Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Masuma Akter","family":"Brishti","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8131-1668","authenticated-orcid":false,"given":"Mousumi","family":"Mandal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7048-4325","authenticated-orcid":false,"given":"Udai Pratap","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tauheed","family":"Ishrat","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-4011","authenticated-orcid":false,"given":"M. Dennis","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2026, February 27). National Diabetes Statistics Report, Available online: https:\/\/gis.cdc.gov\/grasp\/diabetes\/diabetesatlas-statsreport.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.2522\/ptj.20080020","article-title":"Epidemiology of diabetes and diabetes-related complications","volume":"88","author":"Deshpande","year":"2008","journal-title":"Phys. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1042\/CS20160998","article-title":"Sex differences in micro- and macro-vascular complications of diabetes mellitus","volume":"131","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.diabres.2017.07.012","article-title":"Sex and gender differences in therapy of type 2 diabetes","volume":"131","author":"Harreiter","year":"2017","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.amjms.2016.01.011","article-title":"Diabetes and Stroke: Epidemiology, Pathophysiology, Pharmaceuticals and Outcomes","volume":"351","author":"Chen","year":"2016","journal-title":"Am. J. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1161\/CIRCRESAHA.119.315896","article-title":"Metabolic Inflammation and Insulin Resistance in Obesity","volume":"126","author":"Wu","year":"2020","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.immuni.2021.12.013","article-title":"Inflammation in obesity, diabetes, and related disorders","volume":"55","author":"Rohm","year":"2022","journal-title":"Immunity"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nri2925","article-title":"Type 2 diabetes as an inflammatory disease","volume":"11","author":"Donath","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1161\/ATVBAHA.114.303570","article-title":"Mast Cells as Effectors in Atherosclerosis","volume":"35","author":"Bot","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nm1601","article-title":"Mast cells promote atherosclerosis by releasing proinflammatory cytokines","volume":"13","author":"Sun","year":"2007","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Krystel-Whittemore, M., Dileepan, K.N., and Wood, J.G. (2015). Mast Cell: A Multi-Functional Master Cell. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00620"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1161\/CIRCULATIONAHA.106.660472","article-title":"Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E\u2013Deficient Mice","volume":"115","author":"Bot","year":"2007","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kovanen, P.T. (2019). Mast Cells as Potential Accelerators of Human Atherosclerosis-From Early to Late Lesions. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184479"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1182\/blood-2011-07-358432","article-title":"Mast cell modulation of the vascular and lymphatic endothelium","volume":"118","author":"Kunder","year":"2011","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbadis.2010.12.014","article-title":"Mast cells and inflammation","volume":"1822","author":"Theoharides","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.phrs.2016.06.021","article-title":"Histamine in diabetes: Is it time to reconsider?","volume":"111","author":"Pini","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shi, M., and Shi, G.-P. (2012). Different Roles of Mast Cells in Obesity and Diabetes: Lessons from Experimental Animals and Humans. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00007"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"199","DOI":"10.5114\/pjp.2016.63770","article-title":"Are mast cells important in diabetes?","volume":"67","author":"Kempuraj","year":"2016","journal-title":"Pol. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37459","DOI":"10.1074\/jbc.M305877200","article-title":"Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17)","volume":"278","author":"Garton","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_20","first-page":"1","article-title":"Plasma ICAM-1 and VCAM-1 levels in type 2 diabetic patients with and without microalbuminuria","volume":"99","author":"Bruno","year":"2008","journal-title":"Minerva Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"166170","DOI":"10.1016\/j.bbadis.2021.166170","article-title":"VCAM-1 as a predictor biomarker in cardiovascular disease","volume":"1867","author":"Troncoso","year":"2021","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1046\/j.1365-2141.1996.379915.x","article-title":"Elevated plasma levels of vascular cell adhesion molecule-1 (VCAM-1) in diabetic patients with microalbuminuria: A marker of vascular dysfunction and progressive vascular disease","volume":"92","author":"Schmidt","year":"1996","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Katoh, K. (2025). Integrin and Its Associated Proteins as a Mediator for Mechano-Signal Transduction. Biomolecules, 15.","DOI":"10.3390\/biom15020166"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-022-01259-6","article-title":"Targeting integrin pathways: Mechanisms and advances in therapy","volume":"8","author":"Pang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Brishti, M.A., Raghavan, S., Lamar, K., Singh, U.P., Collier, D.M., and Leo, M.D. (2023). Diabetic Endothelial Cell Glycogen Synthase Kinase 3\u03b2 Activation Induces VCAM1 Ectodomain Shedding. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202308.1008.v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"a009191","DOI":"10.1101\/cshperspect.a009191","article-title":"Insulin receptor signaling in normal and insulin-resistant states","volume":"6","author":"Boucher","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_27","unstructured":"De Groot, L.J., Chrousos, G., Dungan, K., Feingold, K.R., Grossman, A., Hershman, J.M., Koch, C., Korbonits, M., McLachlan, R., and New, M. (2000). The Insulin Receptor and Its Signal Transduction Network. Endotext, MDText.com, Inc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1210\/endo.138.11.5473","article-title":"Evidence for involvement of protein kinase C (PKC)-zeta and noninvolvement of diacylglycerol-sensitive PKCs in insulin-stimulated glucose transport in L6 myotubes","volume":"138","author":"Bandyopadhyay","year":"1997","journal-title":"Endocrinology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"30075","DOI":"10.1074\/jbc.272.48.30075","article-title":"Protein kinase C-zeta as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport","volume":"272","author":"Standaert","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H699","DOI":"10.1152\/ajpheart.00071.2010","article-title":"Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease","volume":"299","author":"Hamamdzic","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1161\/CIRCRESAHA.110.217117","article-title":"Activation of protein kinase C isoforms and its impact on diabetic complications","volume":"106","author":"Geraldes","year":"2010","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.2337\/diabetes.54.8.2415","article-title":"Compromised arterial function in human type 2 diabetic patients","volume":"54","author":"Okon","year":"2005","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"C1237","DOI":"10.1152\/ajpcell.00555.2023","article-title":"Extracellular glucose and dysfunctional insulin receptor signaling independently upregulate arterial smooth muscle TMEM16A expression","volume":"326","author":"Raghavan","year":"2024","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/mds.25824","article-title":"A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy","volume":"29","author":"Tolosa","year":"2014","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Brishti, M.A., Vazhappully Francis, F., and Leo, M.D. (2025). Plasma Metabolomic Profiling Reveals Systemic Alterations in a Mouse Model of Type 2 Diabetes. Metabolites, 15.","DOI":"10.3390\/metabo15090564"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s12672-010-0020-z","article-title":"Insulin glargine and NPH insulin increase to a similar degree epithelial cell proliferation and aberrant crypt foci formation in colons of diabetic mice","volume":"1","author":"Nagel","year":"2010","journal-title":"Horm. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.12659\/MSM.907227","article-title":"Comparative Study of Liraglutide and Insulin Glargine on Glycemic Control and Pancreatic \u03b2-Cell Function in db\/db Mice","volume":"24","author":"Li","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_38","first-page":"e57222","article-title":"Isolation of Peritoneum-derived Mast Cells and Their Functional Characterization with Ca2+-imaging and Degranulation Assays","volume":"137","author":"Tsvilovskyy","year":"2018","journal-title":"JoVE"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Meurer, S.K., Ne\u00df, M., Weiskirchen, S., Kim, P., Tag, C.G., Kauffmann, M., Huber, M., and Weiskirchen, R. (2016). Isolation of Mature (Peritoneum-Derived) Mast Cells and Immature (Bone Marrow-Derived) Mast Cell Precursors from Mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158104"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114161","DOI":"10.1016\/j.expneurol.2022.114161","article-title":"The p75 neurotrophin receptor inhibitor, LM11A-31, ameliorates acute stroke injury and modulates astrocytic proNGF","volume":"359","author":"Nasoohi","year":"2023","journal-title":"Exp. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Alhusban, A., Kozak, A., Pillai, B., Ahmed, H., Sayed, M.A., Johnson, M.H., Ishrat, T., Ergul, A., and Fagan, S.C. (2017). Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178867"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1002\/cpz1.78","article-title":"Streptozotocin-Induced Diabetic Models in Mice and Rats","volume":"1","author":"Furman","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.biopha.2017.08.098","article-title":"A practical guide for induction of type-2 diabetes in rat: Incorporating a high-fat diet and streptozotocin","volume":"95","author":"Gheibi","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_44","first-page":"e56672","article-title":"Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT)","volume":"131","author":"Nagy","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/jcbfm.2014.239","article-title":"Mast Cells Promote Blood Brain Barrier Breakdown and Neutrophil Infiltration in a Mouse Model of Focal Cerebral Ischemia","volume":"35","author":"McKittrick","year":"2015","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Arac, A., Grimbaldeston, M.A., Galli, S.J., Bliss, T.M., and Steinberg, G.K. (2019). Meningeal Mast Cells as Key Effectors of Stroke Pathology. Front. Cell Neurosci., 13.","DOI":"10.3389\/fncel.2019.00126"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0166-2236(96)81863-7","article-title":"Mast cells in the brain: Evidence and functional significance","volume":"19","author":"Silver","year":"1996","journal-title":"Trends Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41467-019-14080-7","article-title":"Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance","volume":"11","author":"Yabut","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.cmet.2015.04.013","article-title":"Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance","volume":"21","author":"Gutierrez","year":"2015","journal-title":"Cell Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bbadis.2010.12.012","article-title":"Mast cells and metabolic syndrome","volume":"1822","author":"Zhang","year":"2012","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/nm.1994","article-title":"Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice","volume":"15","author":"Liu","year":"2009","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"E504","DOI":"10.1152\/ajpendo.00462.2018","article-title":"Increased mast cell abundance in adipose tissue of metabolic syndrome: Relevance to the proinflammatory state and increased adipose tissue fibrosis","volume":"316","author":"Gurung","year":"2019","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_53","unstructured":"Hommes, O.R., and Comi, G. (2004). Soluble VCAM-1 Release Indicates Inflammatory Blood-Brain Barrier Pathology and Further Modulates Adhesion. Early Indicators Early Treatments Neuroprotection in Multiple Sclerosis, Springer. Topics in Neuroscience."},{"key":"ref_54","first-page":"4665","article-title":"The Intercellular Cell Adhesion Molecule-1 (ICAM-1) in Lung Cancer: Implications for Disease Progression and Prognosis","volume":"34","author":"Kotteas","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6398","DOI":"10.4049\/jimmunol.161.11.6398","article-title":"Proteolytic Cleavage of ICAM-1 by Human Neutrophil Elastase","volume":"161","author":"Champagne","year":"1998","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0021-9150(03)00253-3","article-title":"Soluble intercellular adhesion molecule 1 and flow-mediated dilatation are related to the estimated risk of coronary heart disease independently from each other","volume":"170","author":"Witte","year":"2003","journal-title":"Atherosclerosis"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000006995","article-title":"Soluble VCAM-1 and E-Selectin, but Not ICAM-1 Discriminate Endothelial Injury in Patients with Documented Coronary Artery Disease","volume":"93","author":"Semaan","year":"2000","journal-title":"Cardiology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1080\/03014460110048530","article-title":"The relationship of soluble ICAM-1, VCAM-1, P-selectin and E-selectin to cardiovascular disease risk factors in healthy men and women","volume":"28","author":"Demerath","year":"2001","journal-title":"Ann. Hum. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4219","DOI":"10.1161\/01.CIR.96.12.4219","article-title":"Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: The Atherosclerosis Risk In Communities (ARIC) study","volume":"96","author":"Hwang","year":"1997","journal-title":"Circulation"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"300060519893858","DOI":"10.1177\/0300060519893858","article-title":"Levels of soluble cell adhesion molecules in type 2 diabetes mellitus patients with macrovascular complications","volume":"48","author":"Hegazy","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4469","DOI":"10.4049\/jimmunol.1400135","article-title":"ICAM-1: Isoforms and Phenotypes","volume":"192","author":"Ramos","year":"2014","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1002\/JLB.2MR0220-549R","article-title":"ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis","volume":"108","author":"Bui","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.1038\/s41467-025-59562-z","article-title":"Dysregulated mast cell activation induced by diabetic milieu exacerbates the progression of diabetic peripheral neuropathy in mice","volume":"16","author":"Yao","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.atherosclerosis.2004.09.008","article-title":"Mast cell tryptase: A new biomarker in patients with stable coronary artery disease","volume":"178","author":"Deliargyris","year":"2005","journal-title":"Atherosclerosis"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Zhi, X., Xu, C., Zhang, H., Tian, D., Li, X., Ning, Y., and Yin, L. (2013). Tryptase promotes atherosclerotic plaque haemorrhage in ApoE-\/- mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060960"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1093\/cvr\/cvq260","article-title":"Mast cell chymase inhibition reduces atherosclerotic plaque progression and improves plaque stability in ApoE\u2212\/\u2212 mice","volume":"89","author":"Bot","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Huang, H., Li, Y., Liang, J., and Finkelman, F.D. (2018). Molecular Regulation of Histamine Synthesis. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01392"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"14188","DOI":"10.1074\/jbc.271.24.14188","article-title":"The human histidine decarboxylase promoter is regulated by gastrin and phorbol 12-myristate 13-acetate through a downstream cis-acting element","volume":"271","author":"Zhang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1002\/ajh.24490","article-title":"Risk of solid cancer, cardiovascular disease, anaphylaxis, osteoporosis and fractures in patients with systemic mastocytosis: A nationwide population-based study","volume":"91","author":"Farkas","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.atherosclerosis.2017.11.030","article-title":"Systemic mastocytosis associates with cardiovascular events despite lower plasma lipid levels","volume":"268","author":"Indhirajanti","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1093\/aje\/kws181","article-title":"Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: A prospective study of 2 matched cohorts","volume":"176","author":"Iribarren","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Hermans, M., Lennep, J.R.V., van Daele, P., and Bot, I. (2019). Mast Cells in Cardiovascular Disease: From Bench to Bedside. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143395"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Ashina, K., Tsubosaka, Y., Nakamura, T., Omori, K., Kobayashi, K., Hori, M., Ozaki, H., and Murata, T. (2015). Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132367"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.arcmed.2014.11.010","article-title":"Role of histaminergic system in blood-brain barrier dysfunction associated with neurological disorders","volume":"45","author":"Aldana","year":"2014","journal-title":"Arch. Med. Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Yue, J., Tan, Y., Huan, R., Guo, J., Yang, S., Deng, M., Xiong, Y., Han, G., Liu, L., and Liu, J. (2023). Mast cell activation mediates blood-brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1090288"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/0026-0495(89)90082-6","article-title":"Plasma histamine concentrations are elevated in patients with diabetes mellitus and peripheral vascular disease","volume":"38","author":"Gill","year":"1989","journal-title":"Metabolism"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e001710","DOI":"10.1136\/bmjdrc-2020-001710","article-title":"Histamine causes an imbalance between pro-angiogenic and anti-angiogenic factors in the retinal pigment epithelium of diabetic retina via H4 receptor\/p38 MAPK axis","volume":"8","author":"Lee","year":"2020","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/0026-0495(90)90124-U","article-title":"Histamine synthesis and catabolism in various tissues in diabetic rats","volume":"39","author":"Gill","year":"1990","journal-title":"Metabolism"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"474","DOI":"10.7150\/ijms.50764","article-title":"Differences in the mechanism of type 1 and type 2 diabetes-induced skin dryness by using model mice","volume":"18","author":"Horikawa","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s12974-020-01833-1","article-title":"Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation","volume":"17","author":"Blasco","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/s12974-023-02887-7","article-title":"Stabilizing histamine release in gut mast cells mitigates peripheral and central inflammation after stroke","volume":"20","author":"Conesa","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1161\/CIRCRESAHA.116.306534","article-title":"Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability","volume":"120","author":"Komarova","year":"2017","journal-title":"Circ. Res."},{"key":"ref_83","first-page":"315709","article-title":"Histamine Blood Concentration in Ischemic Heart Disease Patients","volume":"2011","author":"Zdravkovic","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ejphar.2005.10.060","article-title":"Histamine-induced vasodilation and vasoconstriction in the mesenteric resistance artery of the rat","volume":"529","author":"Jin","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.atherosclerosis.2012.11.029","article-title":"Evaluation of VCAM-1 antibodies as therapeutic agent for atherosclerosis in apolipoprotein E-deficient mice","volume":"226","author":"Park","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Yin, L., Bai, J., Yu, W.J., Liu, Y., Li, H.H., and Lin, Q.Y. (2022). Blocking VCAM-1 Prevents Angiotensin II-Induced Hypertension and Vascular Remodeling in Mice. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.825459"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Qiu, Z.Y., Yu, W.J., Bai, J., and Lin, Q.Y. (2022). Blocking VCAM-1 ameliorates hypertensive cardiac remodeling by impeding macrophage infiltration. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1058268"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1111\/jcmm.12102","article-title":"A novel human anti-VCAM-1 monoclonal antibody ameliorates airway inflammation and remodelling","volume":"17","author":"Lee","year":"2013","journal-title":"J. Cell Mol. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0002-9343(89)80398-5","article-title":"Analysis of plasma histamine levels in patients with mast cell disorders","volume":"87","author":"Friedman","year":"1989","journal-title":"Am. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/ajcn\/85.5.1185","article-title":"Histamine and histamine intolerance","volume":"85","author":"Maintz","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1073\/pnas.1909124117","article-title":"Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming","volume":"117","author":"Noguchi","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"17","DOI":"10.4049\/jimmunol.176.1.17","article-title":"A Key Regulatory Role for Histamine in Experimental Autoimmune Encephalomyelitis: Disease Exacerbation in Histidine Decarboxylase-Deficient Mice","volume":"176","author":"Musio","year":"2006","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"15899","DOI":"10.1038\/s41598-017-16019-8","article-title":"Histamine N-methyltransferase regulates aggression and the sleep-wake cycle","volume":"7","author":"Naganuma","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0925-4439(02)00217-X","article-title":"Augmented lipopolysaccharide-induction of the histamine-forming enzyme in streptozotocin-induced diabetic mice","volume":"1637","author":"Oguri","year":"2003","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. 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