{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:22:08Z","timestamp":1790126528653,"version":"4.0.1"},"reference-count":33,"publisher":"Portland Press Ltd.","issue":"11","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2018\/14544-6"],"award-info":[{"award-number":["2018\/14544-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2017\/22156-3"],"award-info":[{"award-number":["2017\/22156-3"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["304070\/2019-0"],"award-info":[{"award-number":["304070\/2019-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6,11]]},"abstract":"<jats:p>Reduced ventricular function, renin\u2013angiotensin system up-regulation, and sympathoexcitation are hallmarks of heart failure (HF). Recently, we showed that blood\u2013brain barrier (BBB) lesion within autonomic nuclei contributes to autonomic imbalance and that exercise training (T) normalizes BBB function and improves autonomic control. We sought now to identify the mechanism(s) involved in both HF-induced lesion and exercise-induced correction. Wistar rats submitted to coronary artery ligation were, after the development of HF, assigned to losartan (Los) or vehicle (Veh) treatments and simultaneously submitted to T or sedentary (S) protocol. After hemodynamic\/autonomic recordings and evaluation of BBB permeability, brains were harvested for ultrastructural analyses of the barrier (tight junctions\u2019 [TJs] tightness and vesicles trafficking) within capillaries of the hypothalamic paraventricular nucleus. Local angiotensin II (Ang II) expression and activation of microglial cells (IBA-1 immunofluorescence) were also evaluated. High sympathetic activity and pressure variability, reduced parasympathetic control of the heart, elevated BBB permeability, high vesicular trafficking, and TJ weakness exhibited by Veh-S rats were equally corrected in Veh-T, Los-S, and Los-T groups. The increased paraventricular hypothalamic nucleus (PVN) Ang II expression and IBA-1 density in Veh-S group were similarly reduced by T, Los and combination of both. Ang II, colocalized with microglia AT1 receptors, induced their remodeling from disease-associated phenotype in Veh-S rats to homeostatic-surveilling conditions in the other groups. All measured parameters exhibited strong correlations with Ang II availability. Data indicated that changes in PVN Ang II availability induced by HF, exercise, and Los are the key regulator of transcellular and paracellular transport across the BBB.<\/jats:p>","DOI":"10.1042\/cs20242965","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T06:48:47Z","timestamp":1747810127000},"page":"527-543","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Increased absorptive transcytosis and tight junction weakness in heart failure are equally corrected by exercise training and losartan"],"prefix":"10.1042","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6980-0821","authenticated-orcid":false,"given":"Hiviny","family":"de Ataides Raquel","sequence":"first","affiliation":[{"name":"1Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, S\u00e3o Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-000Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6309-6180","authenticated-orcid":false,"given":"Mariana","family":"Makuch-Martins","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, S\u00e3o Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-000Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5188-7794","authenticated-orcid":false,"given":"Sany M.","family":"Perego","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, S\u00e3o Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-000Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo S.","family":"Masson","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, S\u00e3o Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-000Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Jensen","sequence":"additional","affiliation":[{"name":"2School of Medicine, University of Sao Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2978-5406","authenticated-orcid":false,"given":"Lisete C.","family":"Michelini","sequence":"additional","affiliation":[{"name":"1Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, S\u00e3o Paulo, Av. Prof. Lineu Prestes, 1524, SP 05508-000Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"2025061111314038600_CS-2024-2965C1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jchf.2012.10.002","article-title":"Heart failure","volume":"1","author":"Braunwald","year":"2013","journal-title":"JACC Heart Fail."},{"key":"2025061111314038600_CS-2024-2965C2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrcardio.2010.165","article-title":"Epidemiology and risk profile of heart failure","volume":"8","author":"Bui","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"2025061111314038600_CS-2024-2965C3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/SHK.0b013e31824581e8","article-title":"Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure","volume":"37","author":"Fahim","year":"2012","journal-title":"Shock"},{"key":"2025061111314038600_CS-2024-2965C4","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1042\/CS20130294","article-title":"The central renin\u2013angiotensin system and sympathetic nerve activity in chronic heart failure","volume":"126","author":"Zucker","year":"2014","journal-title":"Clin. Sci."},{"key":"2025061111314038600_CS-2024-2965C5","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1161\/CIRCRESAHA.114.302589","article-title":"The autonomic nervous system and heart failure","volume":"114","author":"Florea","year":"2014","journal-title":"Circ. Res."},{"key":"2025061111314038600_CS-2024-2965C6","first-page":"1","article-title":"Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats","volume":"17","author":"Althammer","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"2025061111314038600_CS-2024-2965C7","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1161\/HYPERTENSIONAHA.123.21070","article-title":"Angiotensin ii-mediated neuroinflammation in the hippocampus contributes to neuronal deficits and cognitive impairment in heart failure rats","volume":"80","author":"Althammer","year":"2023","journal-title":"Hypertension"},{"key":"2025061111314038600_CS-2024-2965C8","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s12640-023-00655-2","article-title":"Glial activation, mitochondrial imbalance, and akt\/mtor signaling may be potential mechanisms of cognitive impairment in heart failure mice","volume":"41","author":"Wu","year":"2023","journal-title":"Neurotox. Res."},{"key":"2025061111314038600_CS-2024-2965C9","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1042\/CS20230489","article-title":"Blood\u2013brain barrier lesion \u2013 a novel determinant of autonomic imbalance in heart failure and the effects of exercise training","volume":"137","author":"Raquel","year":"2023","journal-title":"Clin. Sci."},{"key":"2025061111314038600_CS-2024-2965C10","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nrcardio.2009.8","article-title":"Mechanisms by which exercise training benefits patients with heart failure","volume":"6","author":"Crimi","year":"2009","journal-title":"Nat. Rev. Cardiol."},{"key":"2025061111314038600_CS-2024-2965C11","doi-asserted-by":"crossref","first-page":"H781","DOI":"10.1152\/ajpheart.00026.2015","article-title":"Modulation of angiotensin II signaling following exercise training in heart failure","volume":"308","author":"Zucker","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2025061111314038600_CS-2024-2965C12","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2024.1452959","article-title":"Angiotensin II, blood-brain barrier permeability, and microglia interplay during the transition from pre-to hypertensive phase in spontaneously hypertensive rats","volume":"15","author":"Makuch-Martins","year":"2024","journal-title":"Front. Physiol."},{"key":"2025061111314038600_CS-2024-2965C13","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1161\/HYPERTENSIONAHA.113.01743","article-title":"Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier","volume":"63","author":"Biancardi","year":"2014","journal-title":"Hypertension"},{"key":"2025061111314038600_CS-2024-2965C14","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.3389\/fphys.2017.01048","article-title":"Maintenance of blood-brain barrier integrity in hypertension: A novel benefit of exercise training for autonomic control","volume":"8","author":"Buttler","year":"2017","journal-title":"Front. Physiol."},{"key":"2025061111314038600_CS-2024-2965C15","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0137395","article-title":"Early training-induced reduction of angiotensinogen in autonomic areas\u2014the main effect of exercise on brain renin-angiotensin system in hypertensive rats","volume":"10","author":"Chaar","year":"2015","journal-title":"PLoS ONE"},{"key":"2025061111314038600_CS-2024-2965C16","doi-asserted-by":"crossref","first-page":"6241","DOI":"10.1113\/JP272730","article-title":"Exercise training preserves vagal preganglionic neurones and restores parasympathetic tonus in heart failure","volume":"594","author":"Ichige","year":"2016","journal-title":"J. Physiol. (Lond.)"},{"key":"2025061111314038600_CS-2024-2965C17","doi-asserted-by":"crossref","first-page":"R958","DOI":"10.1152\/ajpregu.00104.2011","article-title":"Afferent signaling drives oxytocinergic preautonomic neurons and mediates training-induced plasticity","volume":"301","author":"Cavalleri","year":"2011","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2025061111314038600_CS-2024-2965C18","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0094927","article-title":"Time-dependent effects of training on cardiovascular control in spontaneously hypertensive rats: Role for brain oxidative stress and inflammation and baroreflex sensitivity","volume":"9","author":"Masson","year":"2014","journal-title":"PLoS ONE"},{"key":"2025061111314038600_CS-2024-2965C19","volume-title":"The Rat Brain in Stereotaxic Coordinates","author":"Paxinos","year":"2013","edition":"7th ed"},{"key":"2025061111314038600_CS-2024-2965C20","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2023.1069485","article-title":"Trained hypertensive rats exhibit decreased transcellular vesicle trafficking, increased tight junctions\u2019 density, restored blood-brain barrier permeability and normalized autonomic control of the circulation","volume":"14","author":"Candido","year":"2023","journal-title":"Front. Physiol."},{"key":"2025061111314038600_CS-2024-2965C21","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2020.00309","article-title":"Activity-dependent neuroplastic changes in autonomic circuitry modulating cardiovascular control: The essential role of baroreceptors and chemoreceptors signaling","volume":"11","author":"Rocha-Santos","year":"2020","journal-title":"Front. Physiol."},{"key":"2025061111314038600_CS-2024-2965C22","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/1471-2105-12-230","article-title":"NeurphologyJ: An automatic neuronal morphology quantification method and its application in pharmacological discovery","volume":"12","author":"Ho","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2025061111314038600_CS-2024-2965C23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1152\/physrev.00050.2017","article-title":"Blood-brain barrier: From physiology to disease and back","volume":"99","author":"Sweeney","year":"2019","journal-title":"Physiol. Rev."},{"key":"2025061111314038600_CS-2024-2965C24","doi-asserted-by":"crossref","DOI":"10.1016\/j.imbio.2023.152706","article-title":"TNF-\u03b1 evokes blood-brain barrier dysfunction through activation of Rho-kinase and neurokinin 1 receptor","volume":"228","author":"Gao","year":"2023","journal-title":"Immunobiology"},{"key":"2025061111314038600_CS-2024-2965C25","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/cvr\/cvn119","article-title":"Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-kappaB","volume":"79","author":"Kang","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"2025061111314038600_CS-2024-2965C26","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1113\/JP278864","article-title":"Neuroinflammation in heart failure: new insights for an old disease","volume":"598","author":"D\u00edaz","year":"2020","journal-title":"J. Physiol. (Lond.)"},{"key":"2025061111314038600_CS-2024-2965C27","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1161\/HYPERTENSIONAHA.112.195693","article-title":"Parallel changes in neuronal AT1R and GRK5 expression following exercise training in heart failure","volume":"60","author":"Haack","year":"2012","journal-title":"Hypertension"},{"key":"2025061111314038600_CS-2024-2965C28","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1146\/annurev-physiol-022516-034406","article-title":"Microglia in physiology and disease","volume":"79","author":"Wolf","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"2025061111314038600_CS-2024-2965C29","doi-asserted-by":"crossref","first-page":"104451","DOI":"10.1016\/j.phrs.2019.104451","article-title":"Microglia, autonomic nervous system, immunity and hypertension: Is there a link?","volume":"155","author":"Li","year":"2020","journal-title":"Pharmacol. Res."},{"key":"2025061111314038600_CS-2024-2965C30","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1016\/j.neuron.2022.10.020","article-title":"Microglia states and nomenclature: A field at its crossroads","volume":"110","author":"Paolicelli","year":"2022","journal-title":"Neuron"},{"key":"2025061111314038600_CS-2024-2965C31","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0828-282X(08)70624-X","article-title":"Reporting on sex-based analysis in clinical trials of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker efficacy","volume":"24","author":"Rabi","year":"2008","journal-title":"Can. J. Cardiol."},{"key":"2025061111314038600_CS-2024-2965C32","doi-asserted-by":"crossref","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 New Biol."},{"key":"2025061111314038600_CS-2024-2965C33","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.neuron.2017.03.043","article-title":"Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis","volume":"94","author":"Andreone","year":"2017","journal-title":"Neuron"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/139\/11\/527\/973090\/cs-2024-2965.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/139\/11\/527\/973090\/cs-2024-2965.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T15:31:56Z","timestamp":1749655916000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/139\/11\/527\/236060\/Increased-absorptive-transcytosis-and-tight"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,29]]},"references-count":33,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,6,11]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20242965","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6]]},"published":{"date-parts":[[2025,5,29]]}}}