RT Journal Article
SR 00
ID 10.1161/STROKEAHA.122.037761
A1 Kumar, Apoorva A.
A1 Yeo, Natalie
A1 Whittaker, Max
A1 Attra, Priya
A1 Barrick, Thomas R.
A1 Bridges, Leslie R.
A1 Dickson, Dennis W.
A1 Esiri, Margaret M.
A1 Farris, Chad W.
A1 Graham, Delyth
A1 Lin, Wen Lang
A1 Meijles, Daniel N.
A1 Pereira, Anthony C.
A1 Perry, Gregory
A1 Rosene, Douglas L.
A1 Shtaya, Anan B.
A1 Van Agtmael, Tom
A1 Zamboni, Giovanna
A1 Hainsworth, Atticus H.
T1 Vascular collagen type-IV in hypertension and cerebral small vessel disease
JF Stroke
YR 2022
FD 2022-12
VO 53
IS 12
SP 3696
OP 3705
AB 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.
NO 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).
PB American Heart Association
SN 0039-2499
LK https://eprints.gla.ac.uk/282684/