Molecular and Clinical Sciences Research Institute, St George's University of London, United Kingdom (A.A.K., N.Y., M.W., P.A., T.R.B., L.R.B., D.N.M., A.C.P., G.P., A.B.S., A.H.H.).
Neurology (A.A.K., A.C.P., A.H.H.), St George's University Hospitals NHS Foundation Trust, London, United Kingdom.
Stroke. 2022 Dec;53(12):3696-3705. doi: 10.1161/STROKEAHA.122.037761. Epub 2022 Oct 7.
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 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.
脑小血管病（SVD）在老年人中很常见，可导致腔隙性脑卒中和血管性认知障碍。危险因素包括年龄较大、高血压以及编码胶原 alpha-1(IV)和 alpha-2(IV)的基因变异，这些基因变异被称为胶原-IV，是基底膜的核心成分。我们检验了以下假说：在老年人中，血管胶原-IV 的增加与临床高血压和 SVD 相关，在年轻和老年灵长类动物以及遗传性高血压大鼠中与慢性高血压相关。
我们对一组阿尔茨海默病病理最小化的老年人队列（N=52；21 名女性/31 名男性，年龄 82.8±6.95 岁）中的小动脉中的血管胶原-IV 免疫标记进行了定量。我们还研究了年轻（年龄 6.2-8.3 岁）和老年（17.0-22.7 岁）灵长类动物的存档组织，并比较了慢性高血压动物（18 个月主动脉狭窄）和正常血压动物。我们还比较了遗传性高血压大鼠和正常血压大鼠（年龄 10-12 个月）。
老年人大脑小动脉中的胶原-IV 免疫标记与放射学 SVD 严重程度呈负相关（ρ：-0.427，=0.005），但与高血压病史无关。一般线性模型证实，较低的胶原-IV 与放射学 SVD 呈负相关（<0.017），包括年龄作为协变量以及临床高血压（<0.030）或神经病理学 SVD 诊断（<0.022）作为固定因素。免疫金电子显微镜显示，血管胶原-IV 的减少伴随着纤维胶原（I 型和 III 型）的积累。在年轻和老年灵长类动物中，与年轻正常血压动物相比，老年正常血压动物的大脑胶原-IV 升高（=0.029），但与高血压无关。遗传性高血压大鼠的动脉胶原-IV 与正常血压大鼠无差异。
我们的跨物种数据为散发性 SVD 发病机制提供了新的见解，支持 SVD 中存在不足（而非过多）的动脉胶原-IV，并伴有基质重塑和纤维胶原沉积增加。它们还表明，高血压是 SVD 的主要危险因素，并非通过引起大脑血管胶原-IV 的积累而发挥作用。
