{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:01:32Z","timestamp":1790352092667,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015496","name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas","doi-asserted-by":"publisher","award":["NED24PI02\/2024"],"award-info":[{"award-number":["NED24PI02\/2024"]}],"id":[{"id":"10.13039\/501100015496","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Parkinson\u2019s disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons accompanied by chronic neuroinflammation and \u03b1-SYNUCLEIN (\u03b1-SYN) aggregation. Increasing evidence suggests that cardiovascular comorbidities, including arterial hypertension, may contribute to neurodegenerative processes through vascular dysfunction and sustained inflammatory signaling. However, whether hypertension directly exacerbates \u03b1-SYN-induced neurodegeneration and inflammasome activation remains unclear. Here, we investigated the impact of chronic Angiotensin II (AngII)-induced hypertension in an adeno-associated viral vector (AAV)-based mouse model of PD driven by unilateral overexpression of human \u03b1-SYN in the\n                    <jats:italic>Substantia Nigra<\/jats:italic>\n                    (SN). Chronic AngII infusion produced a robust hypertensive phenotype but did not aggravate \u03b1-SYN-induced loss of tyrosine hydroxylase-positive dopaminergic neurons. Similarly, hypertension failed to modify \u03b1-SYN-driven astrogliosis, microgliosis, or microglial morphological activation. Molecular analyses revealed that \u03b1-SYN overexpression markedly increased the expression of inflammatory mediators and pyroptosis-related genes, including\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    ,\n                    <jats:italic>Asc<\/jats:italic>\n                    ,\n                    <jats:italic>Casp1<\/jats:italic>\n                    ,\n                    <jats:italic>Il1b<\/jats:italic>\n                    ,\n                    <jats:italic>Il18rap<\/jats:italic>\n                    , and\n                    <jats:italic>Gsdmd<\/jats:italic>\n                    . Nevertheless, hypertension did not potentiate these responses. Immunofluorescence analyses further demonstrated that GSDMD expression was predominantly localized in IBA1-positive microglial cells and was significantly elevated following \u03b1-SYN overexpression independently of hypertensive status. Collectively, these findings indicate that chronic AngII-induced hypertension is insufficient to exacerbate early \u03b1-SYN-mediated neurodegeneration, gliosis, or inflammasome-associated pyroptotic pathways in the SN. Our study suggests that \u03b1-SYN pathology itself constitutes the dominant driver of neuroinflammatory activation in this experimental paradigm and that additional vascular or aging-related mechanisms may be required for hypertension to significantly influence PD progression.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1894579","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:11:13Z","timestamp":1790089873000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Angiotensin II-induced hypertension does not exacerbate \u03b1-SYNUCLEIN pathology in a mouse model of Parkinson\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Ignacio","family":"Silva-Llanes","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cSols-Morreale\u201d CSIC-UAM","place":["Madrid, Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Flores-T\u00e9llez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cSols-Morreale\u201d CSIC-UAM","place":["Madrid, Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfrido J.","family":"Arrua","sequence":"additional","affiliation":[{"name":"Dpto. Farmacolog\u00eda, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoual B.","family":"El Jouhari","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz)","place":["Madrid, Spain"]},{"name":"Dpto. Farmacolog\u00eda, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid","place":["Madrid, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, CIBERCV","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Oliver","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, CIBERCV","place":["Madrid, Spain"]},{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas (CSIC)","place":["Madrid, Spain"]},{"name":"Centro Nacional de Investigaciones Cardiovasculares (CNIC)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas (CSIC)","place":["Madrid, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, \u00c1rea Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Briones","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz)","place":["Madrid, Spain"]},{"name":"Dpto. Farmacolog\u00eda, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid","place":["Madrid, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares, CIBERCV","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Lastres-Becker","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cSols-Morreale\u201d CSIC-UAM","place":["Madrid, Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria La Paz (IdiPaz)","place":["Madrid, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, \u00c1rea Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III","place":["Madrid, 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