eprintid: 282684 rev_number: 13 eprint_status: archive userid: 37347 dir: disk0/00/28/26/84 datestamp: 2023-01-23 10:02:58 lastmod: 2023-01-24 09:48:51 status_changed: 2023-01-23 10:02:58 type: article metadata_visibility: show sword_depositor: 37347 creators_name: Kumar, Apoorva A. creators_name: Yeo, Natalie creators_name: Whittaker, Max creators_name: Attra, Priya creators_name: Barrick, Thomas R. creators_name: Bridges, Leslie R. creators_name: Dickson, Dennis W. creators_name: Esiri, Margaret M. creators_name: Farris, Chad W. creators_name: Graham, Delyth creators_name: Lin, Wen Lang creators_name: Meijles, Daniel N. creators_name: Pereira, Anthony C. creators_name: Perry, Gregory creators_name: Rosene, Douglas L. creators_name: Shtaya, Anan B. creators_name: Van Agtmael, Tom creators_name: Zamboni, Giovanna creators_name: Hainsworth, Atticus H. creators_orcid: 0000-0002-7328-4708 creators_orcid: 0000-0003-4282-449X title: Vascular collagen type-IV in hypertension and cerebral small vessel disease ispublished: pub divisions: 25200000 full_text_status: public note: Alzheimer’s Society (United Kingdom; PG146/151), ADDF (Ref 20140901), Alzheimer’s Research UK (PPG2014A-8), and Medical Research Council (MR/R005567/1) to Dr Hainsworth. National Institute for Health and Research Clinical Lectureship (CL-2015-16-001) to A.B. Shtaya. Wellcome Trust (204809/Z/16/Z) to Dr Meijles. National Institutes of Health (P01-NS40256-10, P50-AG16574-14, and P50-AG2571105) to Drs Dickson and Lin. National Institute on Aging (NIA)-funded Program Project (P01-AG000001) and National Institute of Neurological Disorders and Stroke (NINDS)-funded Program Project (P01-NS031649) to Dr Rosene. Italian Ministry of University and Education and “Dipartimenti di eccellenza 2018-2022” to Dr Zamboni. Stroke Association (16VAD-04), Heart Research UK (RG 2664/17/20) and Medical Research Council (MR/R005567/1) to Dr Van Agtmael. This research was funded, in part, by the Wellcome Trust (grant number 204809/Z/16/Z). abstract: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer's pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2-8.3 years) and older (17.0-22.7 years) primates ( ) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10-12 months). Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: -0.427, =0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD ( <0.017), including age as a covariate and either clinical hypertension ( <0.030) or neuropathological SVD diagnosis ( <0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals ( =0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV. date: 2022-12 date_type: published publication: Stroke volume: 53 number: 12 publisher: American Heart Association pagerange: 3696-3705 id_number: 10.1161/STROKEAHA.122.037761 refereed: TRUE issn: 0039-2499 copyright_holders: Copyright © 2022 The Authors prior: First published in Stroke 53(12):3696-3705 repro: Reproduced under a Creative Commons License uniqueid: glaseprints:2022-282684 issn_online: 1524-4628 funding_project_code: 302164 funding_project_code: 300478 funding_project_name: Collagen IV variants and their role in intracerebral haemorrhage in the general population funding_project_name: Elucidation of molecular pathways underlying cardiac disease caused by Col4a1 mutations funding_investigator_name: Tom Van Agtmael funding_investigator_name: Tom Van Agtmael funding_funder_name: Medical Research Council (MRC) funding_funder_name: Heart Research UK (HEARTRES) funding_funder_code: MR/R005567/1 funding_funder_code: RG 2664/17/20 funding_investigator_dept: CAMS - Cardiovascular Science funding_investigator_dept: CAMS - Cardiovascular Science pubmed_id: 36205142 euro_pubmed_id: 36205142 pmcid: PMC9698121 hoa_compliant: 9205 hoa_ref_pan: AB hoa_date_acc: 2022-08-31 hoa_date_pub: 2022-10-07 hoa_date_foa: 2023-01-23 hoa_version_fcd: VoR hoa_exclude: FALSE hoa_gold: TRUE oa_research_materials_ack: No rioxx2_license_ref_input_license_ref: http://creativecommons.org/licenses/by/4.0 rioxx2_license_ref_input_start_date: 2022-10-07 citation: Kumar, A. A. et al. (2022) Vascular collagen type-IV in hypertension and cerebral small vessel disease. Stroke , 53(12), pp. 3696-3705. (doi: 10.1161/STROKEAHA.122.037761 ) (PMID:36205142) (PMCID:PMC9698121) document_url: https://eprints.gla.ac.uk/282684/1/282684.pdf