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Yet VCI research often relies on single-stimulus models, whereas patients experience combined risk factors. We therefore assessed cerebrovascular and cognitive phenotypes in an HFpEF model and investigated underlying mechanisms. Male Lean and Obese ZSF1 rats underwent longitudinal assessments of blood pressure, glucose, cardiac function and behavioural performance. Cerebral blood flow and neurovascular coupling were assessed by laser speckle contrast imaging. White matter integrity, blood\u2013brain barrier (BBB) permeability and vascular density were analyzed by (immuno)histochemistry. Cortical microvessels were isolated for transcriptomic profiling, and selected targets were validated using multiplex in-situ hybridization. Obese rats exhibited neurovascular uncoupling and impaired short- and long-term memory and spatial learning, accompanied by brain atrophy and reduced myelin. BBB permeability increased at 22\u201323\u2009weeks and vascular density at 34\u201335\u2009weeks in Obese versus Lean rats. Transcriptomic analysis of brain microvessels revealed altered processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling, with consistent downregulation of\n                    <jats:italic toggle=\"yes\">Trpv4<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Klf2<\/jats:italic>\n                    . Obese ZSF1 rats develop progressive neurovascular dysfunction associated with HFpEF onset and reduced\n                    <jats:italic toggle=\"yes\">Trpv4<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Klf2<\/jats:italic>\n                    expression in cerebral microvessels, two key vasoprotective genes.\n                  <\/jats:p>","DOI":"10.1177\/0271678x261462714","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T07:29:37Z","timestamp":1781249377000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Downregulation of\n                    <i>Trpv4<\/i>\n                    and\n                    <i>Klf2<\/i>\n                    in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction"],"prefix":"10.1177","author":[{"given":"Sara MP","family":"Lambrichts","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands"},{"name":"Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands"},{"name":"MHeNS \u2013 Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"van der Taelen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands"},{"name":"CARIM \u2013 Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Pastor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Leenders","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Bitsch","sequence":"additional","affiliation":[{"name":"CARIM \u2013 Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Majcher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands"},{"name":"CARIM \u2013 Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Hermes","sequence":"additional","affiliation":[{"name":"MHeNS \u2013 Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands"},{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J","family":"Simmonds","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"van Herwijnen","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Maastricht University, Maastricht, The 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Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hellen P","family":"Steinbusch","sequence":"additional","affiliation":[{"name":"MHeNS \u2013 Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, The Netherlands"},{"name":"Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floor","family":"Arentz","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Anatomy, Research Institute for Medical Innovation, Radboud University Medical Center, Donders Institute for Brain, Cognition &amp; Behaviour, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Wiesmann","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Anatomy, Research Institute for Medical Innovation, Radboud University Medical Center, Donders Institute for Brain, Cognition &amp; Behaviour, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2158-6210","authenticated-orcid":false,"given":"Amanda J","family":"Kiliaan","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Anatomy, Research Institute for Medical Innovation, Radboud University Medical Center, Donders Institute for Brain, Cognition &amp; Behaviour, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Caiment","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Maastricht University, Maastricht, The Netherlands"},{"name":"GROW \u2013 Research institute for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kutmon","sequence":"additional","affiliation":[{"name":"Maastricht Centre for Systems Biology and Bioinformatics (MaCSBio), Maastricht University, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-7064","authenticated-orcid":false,"given":"Elizabeth AV","family":"Jones","sequence":"additional","affiliation":[{"name":"CARIM \u2013 Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands"},{"name":"Department of Cardiovascular 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