Vascular collagen type-IV in hypertension and cerebral small vessel disease

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)

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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.

Item Type:Articles
Additional Information: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).
Glasgow Author(s) Enlighten ID:Van Agtmael, Professor Tom and Graham, Dr Delyth
Authors: Kumar, A. A., Yeo, N., Whittaker, M., Attra, P., Barrick, T. R., Bridges, L. R., Dickson, D. W., Esiri, M. M., Farris, C. W., Graham, D., Lin, W. L., Meijles, D. N., Pereira, A. C., Perry, G., Rosene, D. L., Shtaya, A. B., Van Agtmael, T., Zamboni, G., and Hainsworth, A. H.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Stroke
Publisher:American Heart Association
ISSN (Online):1524-4628
Published Online:07 October 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Stroke 53(12):3696-3705
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302164Collagen IV variants and their role in intracerebral haemorrhage in the general populationTom Van AgtmaelMedical Research Council (MRC)MR/R005567/1CAMS - Cardiovascular Science
300478Elucidation of molecular pathways underlying cardiac disease caused by Col4a1 mutationsTom Van AgtmaelHeart Research UK (HEARTRES)RG 2664/17/20CAMS - Cardiovascular Science