{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:20:09Z","timestamp":1788430809954,"version":"build-2803163510"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":78,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002332","name":"Semmelweis University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002332","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neurovascular uncoupling (NVU) contributes to neurological disorders like Alzheimer\u2019s disease. While a mouse NVU model exists, a reliable rat model critical for cognitive research remains underdeveloped. To address this methodological gap, we investigated a pharmacological approach in rats using the same drugs (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH), L-NG-nitroarginine methyl ester (L-NAME), indomethacin) that proved to be efficacious in mice. The compounds were formulated as a cocktail solution and administered intraperitoneally for 13\u00a0days to aged, cognitively experienced Long-Evans rats. Our goal was to induce NVU while minimizing adverse systemic effects seen previously (e.g., hypertension, intestinal ulceration). The treatment induced only a modest (28%, non-significant) reduction in cerebral hyperaemia, with decreased prostaglandin E2 levels but unchanged 11,12-epoxyeicosatrienoic acid concentration in the brain. Cognitive effects were limited\u2014transient impairment in the 5-choice task but no changes in spontaneous alternation, visual discrimination, cooperation, or motor learning. Significant adverse effects emerged: reduced food intake, weight loss, gastrointestinal malaise, and moderate renal toxicity. Our findings specifically highlight the challenges of achieving sufficient and symptomatically apparent NVU while minimizing systemic toxicity. While partial NVU occurred, this polypharmacy approach had major limitations. A reliable, industrially applicable rat NVU model remains urgently needed to accelerate antidementia drug development.<\/jats:p>","DOI":"10.1038\/s41598-026-58244-0","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:13:13Z","timestamp":1781712793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Translational difficulties in establishing a pharmacologically induced neurovascular uncoupling model in rats"],"prefix":"10.1038","volume":"16","author":[{"given":"Bence Tam\u00e1s","family":"Varga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliz Judit","family":"Ernyey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitta Tekla","family":"Tajti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"G\u00e1sp\u00e1r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Demeter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levente","family":"Koll\u00e1r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mih\u00e1ly","family":"Albert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al\u00e1n","family":"Alp\u00e1r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istv\u00e1n","family":"Gyerty\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"issue":"7321","key":"58244_CR1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature09613","volume":"468","author":"D Attwell","year":"2010","unstructured":"Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468(7321), 232\u2013243. https:\/\/doi.org\/10.1038\/nature09613 (2010).","journal-title":"Nature"},{"issue":"1","key":"58244_CR2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.neuron.2017.07.030","volume":"96","author":"C Iadecola","year":"2017","unstructured":"Iadecola, C. The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease. Neuron 96(1), 17\u201342. https:\/\/doi.org\/10.1016\/j.neuron.2017.07.030 (2017).","journal-title":"Neuron"},{"issue":"7","key":"58244_CR3","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrn.2017.48","volume":"18","author":"K Kisler","year":"2017","unstructured":"Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18(7), 419\u2013434. https:\/\/doi.org\/10.1038\/nrn.2017.48 (2017).","journal-title":"Nat. Rev. Neurosci."},{"issue":"6450","key":"58244_CR4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav9518","volume":"365","author":"R Nortley","year":"2019","unstructured":"Nortley, R. et al. Amyloid \u03b2 oligomers constrict human capillaries in Alzheimer\u2019s disease via signaling to pericytes. Science 365(6450), eaav9518. https:\/\/doi.org\/10.1126\/science.aav9518 (2019).","journal-title":"Science"},{"key":"58244_CR5","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.freeradbiomed.2017.04.026","volume":"108","author":"CF Louren\u00e7o","year":"2017","unstructured":"Louren\u00e7o, C. F., Ledo, A., Barbosa, R. M. & Laranjinha, J. Neurovascular-neuroenergetic coupling axis in the brain: Master regulation by nitric oxide and consequences in aging and neurodegeneration. Free Radic. Biol. Med. 108, 668\u2013682. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2017.04.026 (2017).","journal-title":"Free Radic. Biol. Med."},{"issue":"5","key":"58244_CR6","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1007\/s11357-021-00440-z","volume":"43","author":"S Tarantini","year":"2021","unstructured":"Tarantini, S. et al. Treatment with the BCL-2\/BCL-xL inhibitor senolytic drug ABT263\/Navitoclax improves functional hyperemia in aged mice. GeroScience 43(5), 2427\u20132440. https:\/\/doi.org\/10.1007\/s11357-021-00440-z (2021).","journal-title":"GeroScience"},{"issue":"5","key":"58244_CR7","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1161\/01.str.27.5.971","volume":"27","author":"NJ Alkayed","year":"1996","unstructured":"Alkayed, N. J. et al. Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes. Stroke 27(5), 971\u2013979. https:\/\/doi.org\/10.1161\/01.str.27.5.971 (1996).","journal-title":"Stroke"},{"issue":"11","key":"58244_CR8","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1038\/nn1779","volume":"9","author":"JA Filosa","year":"2006","unstructured":"Filosa, J. A. et al. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat. Neurosci. 9(11), 1397\u20131403. https:\/\/doi.org\/10.1038\/nn1779 (2006).","journal-title":"Nat. Neurosci."},{"issue":"3","key":"58244_CR9","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1556\/2060.2022.00226","volume":"109","author":"BT Varga","year":"2022","unstructured":"Varga, B. T. et al. Introduction of a pharmacological neurovascular uncoupling model in rats based on results of mice. Physiol. Int. 109(3), 405\u2013418. https:\/\/doi.org\/10.1556\/2060.2022.00226 (2022).","journal-title":"Physiol. Int."},{"issue":"3","key":"58244_CR10","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.114.000787","volume":"3","author":"BR Chen","year":"2014","unstructured":"Chen, B. R., Kozberg, M. G., Bouchard, M. B., Shaik, M. A. & Hillman, E. M. C. A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J. Am. Heart Assoc. 3(3), e000787. https:\/\/doi.org\/10.1161\/JAHA.114.000787 (2014).","journal-title":"J. Am. Heart Assoc."},{"issue":"5431","key":"58244_CR11","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1126\/science.285.5431.1276","volume":"285","author":"K Node","year":"1999","unstructured":"Node, K. et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285(5431), 1276\u20131279. https:\/\/doi.org\/10.1126\/science.285.5431.1276 (1999).","journal-title":"Science"},{"key":"58244_CR12","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X251313906","author":"RM Bowen","year":"2025","unstructured":"Bowen, R. M. et al. Control of neurovascular coupling by ATP-sensitive potassium channels. J. Cereb. Blood Flow Metab. https:\/\/doi.org\/10.1177\/0271678X251313906 (2025).","journal-title":"J. Cereb. Blood Flow Metab."},{"issue":"50","key":"58244_CR13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2405965121","volume":"121","author":"D Isaacs","year":"2024","unstructured":"Isaacs, D., Xiang, L., Hariharan, A. & Longden, T. A. KATP channel\u2013dependent electrical signaling links capillary pericytes to arterioles during neurovascular coupling. Proc. Natl. Acad. Sci. U. S. A. 121(50), e2405965121. https:\/\/doi.org\/10.1073\/pnas.2405965121 (2024).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"58244_CR14","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.584135","volume":"11","author":"JL Presa","year":"2020","unstructured":"Presa, J. L., Saravia, F., Bagi, Z. & Filosa, J. A. Vasculo-neuronal coupling and neurovascular coupling at the neurovascular unit: Impact of hypertension. Front. Physiol. 11, 584135. https:\/\/doi.org\/10.3389\/fphys.2020.584135 (2020).","journal-title":"Front. Physiol."},{"issue":"3","key":"58244_CR15","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/nn.4489","volume":"20","author":"K Kisler","year":"2017","unstructured":"Kisler, K. et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20(3), 406\u2013416. https:\/\/doi.org\/10.1038\/nn.4489 (2017).","journal-title":"Nat. Neurosci."},{"key":"58244_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101192","volume":"24","author":"S Tarantini","year":"2019","unstructured":"Tarantini, S. et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 24, 101192. https:\/\/doi.org\/10.1016\/j.redox.2019.101192 (2019).","journal-title":"Redox Biol."},{"issue":"6","key":"58244_CR17","doi-asserted-by":"publisher","first-page":"H1274","DOI":"10.1152\/ajpheart.01067.2011","volume":"302","author":"F Vetri","year":"2012","unstructured":"Vetri, F., Xu, H., Paisansathan, C. & Pelligrino, D. A. Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BK Ca and Kir channels. Am J Physiol-Heart Circulatory Physiol 302(6), H1274\u2013H1284. https:\/\/doi.org\/10.1152\/ajpheart.01067.2011 (2012).","journal-title":"Am J Physiol-Heart Circulatory Physiol"},{"issue":"2","key":"58244_CR18","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1124\/jpet.111.191296","volume":"342","author":"AI Kelly-Cobbs","year":"2012","unstructured":"Kelly-Cobbs, A. I. et al. Cerebral myogenic reactivity and blood flow in type 2 diabetic rats: role of peroxynitrite in hypoxia-mediated loss of myogenic tone. J. Pharmacol. Exp. Ther. 342(2), 407\u2013415. https:\/\/doi.org\/10.1124\/jpet.111.191296 (2012).","journal-title":"J. Pharmacol. Exp. Ther."},{"issue":"5","key":"58244_CR19","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1007\/s11357-020-00233-w","volume":"42","author":"S Wang","year":"2020","unstructured":"Wang, S. et al. Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats. GeroScience 42(5), 1387\u20131410. https:\/\/doi.org\/10.1007\/s11357-020-00233-w (2020).","journal-title":"GeroScience"},{"key":"58244_CR20","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.729201","author":"CF Louren\u00e7o","year":"2021","unstructured":"Louren\u00e7o, C. F. & Laranjinha, J. Nitric oxide pathways in neurovascular coupling under normal and stress conditions in the brain: strategies to rescue aberrant coupling and improve cerebral blood flow. Front. Physiol. https:\/\/doi.org\/10.3389\/fphys.2021.729201 (2021).","journal-title":"Front. Physiol."},{"issue":"5","key":"58244_CR21","doi-asserted-by":"publisher","first-page":"2909","DOI":"10.1007\/s11357-023-00841-2","volume":"45","author":"X Fang","year":"2023","unstructured":"Fang, X. et al. Amyloid beta accumulation in TgF344-AD rats is associated with reduced cerebral capillary endothelial Kir2.1 expression and neurovascular uncoupling. GeroScience 45(5), 2909\u20132926. https:\/\/doi.org\/10.1007\/s11357-023-00841-2 (2023).","journal-title":"GeroScience"},{"issue":"2","key":"58244_CR22","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.tips.2016.10.010","volume":"38","author":"I Gyerty\u00e1n","year":"2017","unstructured":"Gyerty\u00e1n, I. Cognitive \u201cOmics\u201d: Pattern-based validation of potential drug targets. Trends Pharmacol. Sci. 38(2), 113\u2013126. https:\/\/doi.org\/10.1016\/j.tips.2016.10.010 (2017).","journal-title":"Trends Pharmacol. Sci."},{"key":"58244_CR23","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.brainresbull.2020.10.014","volume":"165","author":"I Gyerty\u00e1n","year":"2020","unstructured":"Gyerty\u00e1n, I., Kassai, F., Kozma, K., Kitka, T. & Ernyey, A. J. Procognitive profiling of a serotonin 5-HT6 receptor antagonist in a complex model system in rats: A novel translational approach for clinical prediction. Brain Res. Bull. 165, 238\u2013245. https:\/\/doi.org\/10.1016\/j.brainresbull.2020.10.014 (2020).","journal-title":"Brain Res. Bull."},{"issue":"1","key":"58244_CR24","doi-asserted-by":"publisher","first-page":"23962","DOI":"10.1038\/s41598-021-03372-y","volume":"11","author":"I Gyerty\u00e1n","year":"2021","unstructured":"Gyerty\u00e1n, I. et al. Cognitive profiling and proteomic analysis of the modafinil analogue S-CE-123 in experienced aged rats. Sci. Rep. 11(1), 23962. https:\/\/doi.org\/10.1038\/s41598-021-03372-y (2021).","journal-title":"Sci. Rep."},{"issue":"1","key":"58244_CR25","doi-asserted-by":"publisher","first-page":"12","DOI":"10.31083\/j.jin2101012","volume":"21","author":"F Kassai","year":"2022","unstructured":"Kassai, F., Ernyey, A. J., Kozma, K., Plang\u00e1r, I. & Gyerty\u00e1n, I. Lack of general learning ability factor in a rat test battery measuring a wide spectrum of cognitive domains. J. Integr. Neurosci. 21(1), 12. https:\/\/doi.org\/10.31083\/j.jin2101012 (2022).","journal-title":"J. Integr. Neurosci."},{"issue":"1","key":"58244_CR26","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1007\/s11357-023-00821-6","volume":"46","author":"AJ Ernyey","year":"2024","unstructured":"Ernyey, A. J. et al. Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP). GeroScience 46(1), 417\u2013429. https:\/\/doi.org\/10.1007\/s11357-023-00821-6 (2024).","journal-title":"GeroScience"},{"issue":"21\u201322","key":"58244_CR27","doi-asserted-by":"publisher","first-page":"4059","DOI":"10.1007\/s00213-015-3954-6","volume":"232","author":"SK Janhunen","year":"2015","unstructured":"Janhunen, S. K. et al. The subchronic phencyclidine rat model: Relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia. Psychopharmacology 232(21\u201322), 4059\u20134083. https:\/\/doi.org\/10.1007\/s00213-015-3954-6 (2015).","journal-title":"Psychopharmacology"},{"issue":"4","key":"58244_CR28","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1007\/BF02245257","volume":"107","author":"M Sarter","year":"1992","unstructured":"Sarter, M., Hagan, J. & Dudchenko, P. Behavioral screening for cognition enhancers: From indiscriminate to valid testing: II. Psychopharmacology 107(4), 461\u2013473. https:\/\/doi.org\/10.1007\/BF02245257 (1992).","journal-title":"Psychopharmacology"},{"key":"58244_CR29","doi-asserted-by":"publisher","first-page":"S217","DOI":"10.1016\/j.euroneuro.2020.09.283","volume":"40","author":"I Gyerty\u00e1n","year":"2020","unstructured":"Gyerty\u00e1n, I., Kozma, K., Kassai, F. & Ernyey, A. J. P.377 Rats with long learning experience showed resistance to the impairing effect of MK-801 in several cognitive assays. Eur. Neuropsychopharmacol. 40, S217. https:\/\/doi.org\/10.1016\/j.euroneuro.2020.09.283 (2020).","journal-title":"Eur. Neuropsychopharmacol."},{"key":"58244_CR30","doi-asserted-by":"publisher","first-page":"S404","DOI":"10.1016\/j.euroneuro.2021.10.519","volume":"53","author":"I Gyerty\u00e1n","year":"2021","unstructured":"Gyerty\u00e1n, I., Kassai, F., G\u00e1sp\u00e1r, A., Varga, B. T. & Ernyey, A. J. P.0549 A complex experimental design for measuring the learning impairing effect of repeat dose scopolamine in experienced aged rats. Eur. Neuropsychopharmacol. 53, S404. https:\/\/doi.org\/10.1016\/j.euroneuro.2021.10.519 (2021).","journal-title":"Eur. Neuropsychopharmacol."},{"key":"58244_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.nsa.2022.100355","volume":"1","author":"A G\u00e1sp\u00e1r","year":"2022","unstructured":"G\u00e1sp\u00e1r, A., Ernyey, A. J., Tajti, B. T., Varga, B. T. & Gyerty\u00e1n, I. Cognitive characterization of the scopolamine-induced dementia model in experienced rats. Neurosci. Appl. 1, 100355. https:\/\/doi.org\/10.1016\/j.nsa.2022.100355 (2022).","journal-title":"Neurosci. Appl."},{"issue":"11","key":"58244_CR32","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1038\/jcbfm.2015.162","volume":"35","author":"S Tarantini","year":"1871","unstructured":"Tarantini, S. et al. Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J. Cereb. Blood Flow Metab. 35(11), 1871\u20131881. https:\/\/doi.org\/10.1038\/jcbfm.2015.162 (1871).","journal-title":"J. Cereb. Blood Flow Metab."},{"issue":"1","key":"58244_CR33","doi-asserted-by":"publisher","first-page":"20247","DOI":"10.1038\/s41598-022-24292-5","volume":"12","author":"A G\u00e1sp\u00e1r","year":"2022","unstructured":"G\u00e1sp\u00e1r, A. et al. Performance of the intracerebroventricularly injected streptozotocin Alzheimer\u2019s disease model in a translationally relevant, aged and experienced rat population. Sci. Rep. 12(1), 20247. https:\/\/doi.org\/10.1038\/s41598-022-24292-5 (2022).","journal-title":"Sci. Rep."},{"issue":"4","key":"58244_CR34","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1152\/jn.00474.2009","volume":"103","author":"S Vijayan","year":"2074","unstructured":"Vijayan, S., Hale, G. J., Moore, C. I., Brown, E. N. & Wilson, M. Activity in the barrel cortex during active behavior and sleep. J. Neurophysiol. 103(4), 2074\u20132084. https:\/\/doi.org\/10.1152\/jn.00474.2009 (2074).","journal-title":"J. Neurophysiol."},{"key":"58244_CR35","unstructured":"\u2018Rat Epoxyeicosatrienoic acids ELISA kit (E02E0166)\u2019, Shanghai BlueGene Biotech CO., LTD. Accessed: Jul. 06, 2025. [Online]. Available: https:\/\/www.elisakit.cc\/products\/rat-epoxyeicosatrienoic-acids-elisa-kit\/"},{"issue":"3","key":"58244_CR36","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/s11357-019-00073-3","volume":"41","author":"AJ Ernyey","year":"2019","unstructured":"Ernyey, A. J. et al. Following of aging process in a new motor skill learning model, \u201cpot jumping\u201d in rats. GeroScience 41(3), 309\u2013319. https:\/\/doi.org\/10.1007\/s11357-019-00073-3 (2019).","journal-title":"GeroScience"},{"key":"58244_CR37","unstructured":"\u2018Home | Cayman Chemical\u2019. Accessed: Feb. 13, 2025. [Online]. Available: https:\/\/www.caymanchem.com\/"},{"key":"58244_CR38","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00913","author":"CF Louren\u00e7o","year":"2018","unstructured":"Louren\u00e7o, C. F., Ledo, A., Caetano, M., Barbosa, R. M. & Laranjinha, J. Age-dependent impairment of neurovascular and neurometabolic coupling in the hippocampus. Front. Physiol. https:\/\/doi.org\/10.3389\/fphys.2018.00913 (2018).","journal-title":"Front. Physiol."},{"issue":"5","key":"58244_CR39","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1007\/s11357-019-00111-0","volume":"41","author":"A Csiszar","year":"2019","unstructured":"Csiszar, A., Yabluchanskiy, A., Ungvari, A., Ungvari, Z. & Tarantini, S. Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice. GeroScience 41(5), 609\u2013617. https:\/\/doi.org\/10.1007\/s11357-019-00111-0 (2019).","journal-title":"GeroScience"},{"issue":"4","key":"58244_CR40","doi-asserted-by":"publisher","first-page":"3959","DOI":"10.3390\/ijms24043959","volume":"24","author":"J Youwakim","year":"2023","unstructured":"Youwakim, J., Vallerand, D. & Girouard, H. Neurovascular coupling in hypertension is impaired by IL-17A through oxidative stress. Int. J. Mol. Sci. 24(4), 3959. https:\/\/doi.org\/10.3390\/ijms24043959 (2023).","journal-title":"Int. J. Mol. Sci."},{"issue":"11","key":"58244_CR41","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1177\/153537020623101112","volume":"231","author":"H Huang","year":"2006","unstructured":"Huang, H. et al. Epoxyeicosatrienoic acid inhibition alters renal hemodynamics during pregnancy. Exp. Biol. Med. 231(11), 1744\u20131752. https:\/\/doi.org\/10.1177\/153537020623101112 (2006).","journal-title":"Exp. Biol. Med."},{"issue":"6","key":"58244_CR42","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1161\/HYPERTENSIONAHA.108.123570","volume":"54","author":"EL Liclican","year":"2009","unstructured":"Liclican, E. L. et al. Inhibition of the adenosine2A receptor-epoxyeicosatrienoic acid pathway renders Dahl salt-resistant rats hypertensive. Hypertension 54(6), 1284\u20131290. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.108.123570 (2009).","journal-title":"Hypertension"},{"issue":"3","key":"58244_CR43","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1002\/hep.28686","volume":"64","author":"M Di Pascoli","year":"2016","unstructured":"Di Pascoli, M. et al. Inhibition of epoxyeicosatrienoic acid production in rats with cirrhosis has beneficial effects on portal hypertension by reducing splanchnic vasodilation. Hepatology 64(3), 923\u2013930. https:\/\/doi.org\/10.1002\/hep.28686 (2016).","journal-title":"Hepatology"},{"issue":"1","key":"58244_CR44","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1111\/j.1440-1681.2010.05464.x","volume":"38","author":"G-G Yu","year":"2011","unstructured":"Yu, G.-G. et al. Cytochrome P450 2J3\/epoxyeicosatrienoic acids mediate the cardioprotection induced by ischaemic post-conditioning, but not preconditioning, in the rat. Clin. Exp. Pharmacol. Physiol. 38(1), 63\u201370. https:\/\/doi.org\/10.1111\/j.1440-1681.2010.05464.x (2011).","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"58244_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111978","volume":"142","author":"TIM Ragab","year":"2021","unstructured":"Ragab, T. I. M. et al. Renoprotective and therapeutic effects of newly water, ethanol, and butanol ginseng fractions in hypertensive and chronic kidney disease with L-NAME. Biomed. Pharmacother. 142, 111978. https:\/\/doi.org\/10.1016\/j.biopha.2021.111978 (2021).","journal-title":"Biomed. Pharmacother."},{"issue":"9","key":"58244_CR46","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1093\/ndt\/15.9.1337","volume":"15","author":"RP van Dokkum","year":"2000","unstructured":"van Dokkum, R. P., Jacob, H. J. & Provoost, A. P. Blood pressure and the susceptibility to renal damage after unilateral nephrectomy and L-NAME-induced hypertension in rats. Nephrol. Dial. Transplant. 15(9), 1337\u20131343. https:\/\/doi.org\/10.1093\/ndt\/15.9.1337 (2000).","journal-title":"Nephrol. Dial. Transplant."},{"issue":"5","key":"58244_CR47","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1111\/j.1472-8206.2010.00887.x","volume":"25","author":"AC Ribeiro-Rama","year":"2011","unstructured":"Ribeiro-Rama, A. C. et al. Hepatic and renal toxicities of indomethacin acid, salt form and complexed forms with hydroxypropyl-\u03b2-cyclodextrin on Wistar rats after oral administration. Fundam. Clin. Pharmacol. 25(5), 599\u2013607. https:\/\/doi.org\/10.1111\/j.1472-8206.2010.00887.x (2011).","journal-title":"Fundam. Clin. Pharmacol."},{"issue":"3","key":"58244_CR48","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1172\/JCI117421","volume":"94","author":"Y Agmon","year":"1994","unstructured":"Agmon, Y., Peleg, H., Greenfeld, Z., Rosen, S. & Brezis, M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat.. J. Clin. Invest. 94(3), 1069\u20131075. https:\/\/doi.org\/10.1172\/JCI117421 (1994).","journal-title":"J. Clin. Invest."},{"key":"58244_CR49","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00187","author":"J Li","year":"2014","unstructured":"Li, J. et al. Pharmacological manipulation of arachidonic acid-epoxygenase results in divergent effects on renal damage. Front. Pharmacol. https:\/\/doi.org\/10.3389\/fphar.2014.00187 (2014).","journal-title":"Front. Pharmacol."},{"key":"58244_CR50","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.taap.2017.09.007","volume":"334","author":"SH Hammoud","year":"2017","unstructured":"Hammoud, S. H., Omar, A. G., Eid, A. A. & El-Mas, M. M. CYP4A\/CYP2C modulation of the interaction of calcium channel blockers with cyclosporine on EDHF-mediated renal vasodilations in rats. Toxicol. Appl. Pharmacol. 334, 110\u2013119. https:\/\/doi.org\/10.1016\/j.taap.2017.09.007 (2017).","journal-title":"Toxicol. Appl. Pharmacol."},{"issue":"50","key":"58244_CR51","doi-asserted-by":"publisher","first-page":"10081","DOI":"10.1523\/JNEUROSCI.1357-19.2019","volume":"39","author":"K Han","year":"2019","unstructured":"Han, K. et al. Neurovascular coupling under chronic stress is modified by altered GABAergic interneuron activity. J. Neurosci. 39(50), 10081\u201310095. https:\/\/doi.org\/10.1523\/JNEUROSCI.1357-19.2019 (2019).","journal-title":"J. Neurosci."},{"key":"58244_CR52","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2025.0801","author":"T Zhao","year":"2025","unstructured":"Zhao, T. et al. Crossing pathological boundaries: Multi-target restoration of the neurovascular unit in Alzheimer\u2019s and vascular dementia-from modern therapeutics to traditional Chinese medicine. Aging Dis. https:\/\/doi.org\/10.14336\/AD.2025.0801 (2025).","journal-title":"Aging Dis."},{"issue":"1","key":"58244_CR53","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s12974-026-03723-4","volume":"23","author":"H Lu","year":"2026","unstructured":"Lu, H. et al. Capillary-associated microglia in neurovascular coupling: Localization, mechanisms, and disease implications. J. Neuroinflammation 23(1), 86. https:\/\/doi.org\/10.1186\/s12974-026-03723-4 (2026).","journal-title":"J. Neuroinflammation"},{"key":"58244_CR54","doi-asserted-by":"publisher","first-page":"462","DOI":"10.3389\/fnins.2015.00462","volume":"9","author":"S Lee","year":"2015","unstructured":"Lee, S. et al. Chronic stress decreases cerebrovascular responses during rat Hindlimb electrical stimulation. Front. Neurosci. 9, 462. https:\/\/doi.org\/10.3389\/fnins.2015.00462 (2015).","journal-title":"Front. Neurosci."},{"issue":"2","key":"58244_CR55","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1096\/fj.10-171488","volume":"25","author":"Y Deng","year":"2011","unstructured":"Deng, Y. et al. Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J. 25(2), 703\u2013713. https:\/\/doi.org\/10.1096\/fj.10-171488 (2011).","journal-title":"FASEB J."},{"key":"58244_CR56","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2013.02.003","author":"A Askari","year":"2013","unstructured":"Askari, A., Thomson, S. J., Edin, M. L., Zeldin, D. C. & Bishop-Bailey, D. Roles of the epoxygenase CYP2J2 in the endothelium. Prostaglandins Other Lipid Mediat. https:\/\/doi.org\/10.1016\/j.prostaglandins.2013.02.003 (2013).","journal-title":"Prostaglandins Other Lipid Mediat."},{"issue":"4","key":"58244_CR57","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1124\/pr.113.007781","volume":"66","author":"I Fleming","year":"2014","unstructured":"Fleming, I. The pharmacology of the cytochrome P450 epoxygenase\/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease. Pharmacol. Rev. 66(4), 1106\u20131140. https:\/\/doi.org\/10.1124\/pr.113.007781 (2014).","journal-title":"Pharmacol. Rev."},{"issue":"12","key":"58244_CR58","doi-asserted-by":"publisher","first-page":"3873","DOI":"10.3390\/molecules27123873","volume":"27","author":"Z Shi","year":"2022","unstructured":"Shi, Z., He, Z. & Wang, D. W. CYP450 epoxygenase metabolites, epoxyeicosatrienoic acids, as novel anti-inflammatory mediators. Molecules 27(12), 3873. https:\/\/doi.org\/10.3390\/molecules27123873 (2022).","journal-title":"Molecules"},{"issue":"1","key":"58244_CR59","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1177\/0192623308329474","volume":"37","author":"ZA Radi","year":"2009","unstructured":"Radi, Z. A. Pathophysiology of cyclooxygenase inhibition in animal models. Toxicol. Pathol. 37(1), 34\u201346. https:\/\/doi.org\/10.1177\/0192623308329474 (2009).","journal-title":"Toxicol. Pathol."},{"issue":"2","key":"58244_CR60","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/ni0202-102a","volume":"3","author":"M Schneemann","year":"2002","unstructured":"Schneemann, M. & Schoedon, G. Species differences in macrophage NO production are important. Nat. Immunol. 3(2), 102\u2013102. https:\/\/doi.org\/10.1038\/ni0202-102a (2002).","journal-title":"Nat. Immunol."},{"issue":"11","key":"58244_CR61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003950","volume":"9","author":"GL Zhou","year":"2013","unstructured":"Zhou, G. L. et al. Deletion of the murine cytochrome P450 Cyp2j locus by fused BAC-mediated recombination identifies a role for Cyp2j in the pulmonary vascular response to hypoxia. PLOS Genet. 9(11), e1003950. https:\/\/doi.org\/10.1371\/journal.pgen.1003950 (2013).","journal-title":"PLOS Genet."},{"issue":"8","key":"58244_CR62","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1124\/dmd.115.064139","volume":"43","author":"JP Graves","year":"2015","unstructured":"Graves, J. P. et al. Quantitative polymerase chain reaction analysis of the mouse Cyp2j subfamily: Tissue distribution and regulation. Drug Metab. Dispos. 43(8), 1169\u20131180. https:\/\/doi.org\/10.1124\/dmd.115.064139 (2015).","journal-title":"Drug Metab. Dispos."},{"issue":"5","key":"58244_CR63","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/jcbfm.2012.4","volume":"32","author":"C Lecrux","year":"2012","unstructured":"Lecrux, C., Kocharyan, A., Sandoe, C. H., Tong, X.-K. & Hamel, E. Pyramidal cells and cytochrome P450 epoxygenase products in the neurovascular coupling response to basal forebrain cholinergic input. J. Cereb. Blood Flow Metab. 32(5), 896\u2013906. https:\/\/doi.org\/10.1038\/jcbfm.2012.4 (2012).","journal-title":"J. Cereb. Blood Flow Metab."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58244-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58244-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58244-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:00:42Z","timestamp":1788429642000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58244-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["58244"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-58244-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"assertion":[{"value":"4 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"27671"}}