Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.
Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.
复制标题
作者：
脑小血管疾病（SVD）在老年人中很常见，会导致腔隙性中风和血管性认知障碍。危险因素包括年老、高血压和编码胶原蛋白 α-1(IV) 和 α-2(IV) 的基因 COL4A1/COL4A2 变异，此处称为胶原蛋白-IV，是基底膜的核心成分。我们检验了这样的假设：血管 IV 型胶原蛋白增加与老年人的临床高血压和 SVD 以及年轻和老年灵长类动物和遗传性高血压大鼠的慢性高血压有关。我们对一组患有轻微阿尔茨海默病的老年人（N=52；21F/31M，年龄 82.8±6.95 岁）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（年龄范围 6.2-8.3 岁）和年长（17.0-22.7 岁）灵长类动物 (M mulatta) 的档案组织，并将慢性高血压动物（18 个月主动脉瓣狭窄）与正常血压动物进行比较。我们还比较了遗传性高血压和血压正常的大鼠（10-12 个月大）。老年人脑小动脉中的 IV 型胶原蛋白免疫标记与放射学 SVD 严重程度呈负相关（ρ：-0.427，P=0.005），但与高血压病史无关。一般线性模型证实了较低的 IV 型胶原蛋白与放射学 SVD 呈负相关（P < 0.017），包括作为协变量的年龄以及作为固定因素的临床高血压（P < 0.030）或神经病理学 SVD 诊断（P < 0.022）。免疫金电子显微镜显示，血管 IV 型胶原蛋白的减少伴随着纤维状胶原蛋白（I 型和 III 型）的积累。在年轻和老年灵长类动物中，与年轻血压正常的动物相比，老年血压正常的动物的脑 IV 型胶原蛋白升高（P=0.029），但与高血压无关。就动脉 IV 型胶原蛋白而言，遗传性高血压大鼠与血压正常大鼠没有差异。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 中动脉 IV 型胶原蛋白不足（而不是过多），并伴随着纤维状胶原蛋白沉积增加的基质重塑。他们还表明，高血压是 SVD 的主要危险因素，但它并不是通过引起脑血管 IV 型胶原蛋白的积累来发挥作用。
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 COL4A1/COL4A2 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 (M mulatta) 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, P=0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD (P<0.017), including age as a covariate and either clinical hypertension (P<0.030) or neuropathological SVD diagnosis (P<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 (P=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.