J Clin Invest. 2024;134(10):e172841. https://doi.org/10.1172/JCI172841.
《临床研究杂志》. 2024;134(10):e172841. https://doi.org/10.1172/JCI172841.

Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately $25\mathrm{\%}$$25\mathrm{\%}$25%25 \% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3, HTRA1, and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.
脑小血管病（cSVD）是一组异质性年龄相关性小血管病变，影响多个脑区。疾病表现从神经影像学检查中偶然发现的病变（如白质高信号、小深部梗死、微出血或扩大周围血管间隙）到严重残疾和认知障碍。cSVD占缺血性卒中的 $25\mathrm{\%}$$25\mathrm{\%}$25%25 \% ，是自发性脑内出血的主要原因，也是痴呆最重要的血管病因。尽管其高发病率和潜在的治疗窗口期，目前仍缺乏基于机制的治疗方法。本文概述了该领域最近的进展。我们总结了近期数据，强调了涉及NOTCH3、HTRA1和COL4A1/A2基因的单基因和多因素cSVD之间的显著连续性。从血管中心视角出发，我们探讨了危险因素、血管结构与功能改变及疾病表现之间的可能因果关系，并强调了部分重大知识空白。尽管内皮功能障碍被公认为cSVD的核心特征，但平滑肌细胞、周细胞及其他血管周围细胞的贡献仍需进一步研究。

Cerebral small vessel disease (cSVD) is an umbrella term for a collection of distinct diseases with overlapping phenotypes caused by intrinsic lesions of intracranial vessels. cSVDs are commonly classified into sporadic and hereditary cerebral amyloid angiopathy (CAA) and cSVD distinct from CAA (1). The latter classification - a larger group of pathologies commonly related to aging, hypertension, or genetic factors - is the focus of this Review.
脑小血管病（cSVD）是一组由颅内血管内在病变引起的、具有重叠表型的不同疾病的统称。cSVD通常分为散发性和遗传性脑淀粉样血管病（CAA）以及与CAA不同的cSVD（1）。后者分类——一个与衰老、高血压或遗传因素密切相关的更大病理群体——是本综述的重点。
cSVDs are primarily defined by their hallmark features on brain MRI, including white matter (WM) hyperintensities (WMHs), small subcortical infarcts or lacunes, visible perivascular spaces (PVSs), microbleeds, intracerebral hemorrhage (ICH), and brain atrophy (Figure 1) (2). However, cSVD lesions detected by conventional MRI likely represent only the tip of the iceberg. Indeed, more sensitive imaging techniques such as diffusion tensor imaging (DTI) can detect altered diffusion properties in areas that appear normal on conventional MRI (3). The most common clinical manifestations associated with cSVDs include stroke, related to the occurrence of a small subcortical infarct; motor impairment; imbalance; and cognitive impairment. Cognitive deficits are predominantly characterized by altered executive functions and reduced processing speed (4). Other neuropsychiatric symptoms, such as apathy (a syndrome of reduced motivation), fatigue, depression, and delirium, are increasingly recognized as important features (5). The full spectrum of cSVD manifestations ranges from covert cSVD (brain lesions incidentally detected on
cSVD的主要特征主要通过脑部MRI检查表现出来，包括白质高信号（WMHs）、小脑皮层下梗死或腔隙、可见的血管周围间隙（PVSs）、微出血、脑内出血（ICH）以及脑萎缩（图1）（2）。然而，传统MRI检测到的cSVD病变可能仅是冰山一角。事实上，更敏感的成像技术如扩散张量成像（DTI）可在传统MRI显示正常的区域检测到扩散特性异常（3）。与cSVD相关的最常见临床表现包括中风（与小脑皮质下梗死发生相关）、运动障碍、平衡障碍及认知障碍。认知缺陷主要表现为执行功能障碍和处理速度减慢（4）。其他神经精神症状，如淡漠（一种动机减退综合征）、疲劳、抑郁和谵妄，越来越被认为是重要特征（5）。cSVD的全部表现谱系从隐性cSVD（在常规MRI中偶然发现的脑病变）到

brain MRI, especially in individuals 50-55 years or older with no overt clinical symptoms) to disability and dementia (6). Hence, cSVDs are thought to progress silently for many years before becoming clinically symptomatic, a conclusion supported by the natural history of monogenic forms that are largely indistinguishable from sporadic cSVDs (7).
脑部MRI（尤其是对50至55岁及以上且无明显临床症状的个体）与残疾和痴呆（6）之间存在关联。因此，cSVDs被认为会在数年内悄然进展，直至出现临床症状，这一结论得到了单基因形式的自然史研究的支持，这些形式与散发性cSVDs在临床表现上几乎无法区分（7）。
cSVDs are among the most prevalent disorders that impact brain health at the population level, and their prevalence increases with age, affecting approximately $5\mathrm{\%}$$5\mathrm{\%}$5%5 \% of those over 50 years old and almost everyone over 90 years old. Broadly speaking, cSVDs account for approximately $25\mathrm{\%}$$25\mathrm{\%}$25%25 \% of ischemic strokes and the vast majority of spontaneous ICHs in aged individuals; they are also the second-most common cause of dementia after Alzheimer disease (4). Despite their high prevalence and potentially long therapeutic window, there are as yet no mechanism-based treatments for these devastating diseases. One major reason for this lack of treatment options is the complex multifactorial roots of cSVDs, which go well beyond blood clotting and vessel rupture.
cSVDs是影响人群脑健康最常见的疾病之一，其患病率随年龄增长而增加，约占50岁以上人群的 $5\mathrm{\%}$$5\mathrm{\%}$5%5 \% ，且几乎所有90岁以上人群均受影响。从广义上讲，cSVDs约占缺血性中风的 $25\mathrm{\%}$$25\mathrm{\%}$25%25 \% ，并占老年人群中绝大多数的自发性脑出血（ICH）；它们也是继阿尔茨海默病之后导致痴呆的第二大常见原因（4）。尽管这些疾病的患病率极高且可能存在较长的治疗窗口期，但目前仍缺乏基于机制的治疗方法。治疗选择匮乏的主要原因在于cSVDs的复杂多因素病因，其影响远超血液凝固和血管破裂。

Thanks to large-scale biomedical databases, international collaborative networks, and the affordability of high-throughput genotyping and sequencing, the past decade has witnessed major advances in our understanding of the genetic landscape of cSVDs. Technological developments in neuroimaging have enabled clinicians to probe functional abnormalities of small brain vessels in individual patients. Experimental studies, aided by newly developed models and cutting-edge imaging approaches, have identified novel mechanisms of vascular pathology in individual forms of cSVD as well as shared mechanisms among them. Taking a vessel-centric view, we summarize these advances and discuss the mechanisms linking structural and functional changes in brain vessels to disease manifestations. We conclude by highlighting some knowledge gaps and future perspectives.
得益于大规模生物医学数据库、国际协作网络以及高通量基因分型和测序技术的可及性，过去十年在理解cSVDs的遗传学特征方面取得了重大进展。神经影像学技术的进步使临床医生能够在个体患者中探查小脑血管的功能异常。借助新开发的模型和前沿成像技术，实验研究已揭示了不同类型cSVD中血管病理学的全新机制，以及这些机制之间的共同特征。从血管中心视角出发，我们总结了这些进展，并探讨了脑血管结构与功能改变与疾病表现之间的关联机制。最后，我们强调了当前研究的知识空白及未来研究方向。

Figure 1. Neuroimaging features of cSVDs. In 2013, a group of experts published Standards for Reporting Vascular Changes on Neuroimaging (STRIVE-1) (2) - an attempt to harmonize terminology and definitions of key MRI features associated with cSVDs. These features include the following: white matter hyperintensities (WMHs) on T2-weighted MRI sequences (yellow); recent, small subcortical infarcts; subcortical lacunes of presumed vascular origin ( $3-15\mathrm{mm}$$3-15\mathrm{mm}$3-15mm3-15 \mathrm{~mm} fluid-filled cavities) (dark tan), likely the end result of a small subcortical infarct or microhemorrhage; perivascular (fluid-filled) spaces that follow the course of small perforating vessels (purple); microbleeds ( $2-5\mathrm{mm}$$2-5\mathrm{mm}$2-5mm2-5 \mathrm{~mm} diameter), detected as hypointense lesions on T2* images or susceptibility-weighted sequences (red); intracerebral hemorrhage (ICH) (red); and brain atrophy.
图1. cSVD的神经影像学特征。2013年，一群专家发表了《神经影像学血管改变报告标准》（STRIVE-1）（2）——旨在统一与cSVD相关的关键MRI特征的术语和定义。这些特征包括以下内容：T2加权MRI序列中的白质高信号（WMHs）（黄色）；近期发生的皮层下小梗死；疑似血管源性的皮层下腔隙（ $3-15\mathrm{mm}$$3-15\mathrm{mm}$3-15mm3-15 \mathrm{~mm} 液体充盈的腔隙）（深棕色），可能是小皮层下梗死或微出血的最终结果；沿小穿通血管走行分布的血管周围（含液体）间隙（紫色）；微出血（直径 $2-5\mathrm{mm}$$2-5\mathrm{mm}$2-5mm2-5 \mathrm{~mm} ），在T2*序列或易感性加权序列中表现为低信号病灶（红色）；脑内出血（ICH）（红色）；以及脑萎缩。

In recent years, increasing numbers of genes have been associated with cSVDs (8-18). Notably, mutations in four genes - NOTCH3, HTRA1 (high-temperature requirement A serine peptidase 1), COL4A1 (collagen type IV $\alpha 1$$\alpha 1$alpha1\alpha 1 ), and COL4A2 - account for the vast majority of monogenic adult-onset cSVDs (Table 1) (19-22). Among these monogenic forms, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by dominant missense mutations that alter the number of cysteines in one of the 34 EGF repeats in the extracellular domain of the NOTCH3 protein (NOTCH3 ${}^{\text{ECD}}$${}^{\text{ECD }}$^("ECD "){ }^{\text {ECD }} ), is the most frequent (23). NOTCH3 is a transmembrane receptor predominantly expressed in mural cells - smooth muscle cells (SMCs) and pericytes - of small vessels. CADASIL mutations stereotypically lead to abnormal aggregation and accumulation of NOTCH3 and other extracellular matrix (ECM) proteins around mural cells, and cause pathology likely through a gain-of-function mechanism (24-26). Interestingly, recessive loss-of-function mutations in NOTCH3 are associated with a rare and severe form of cSVD with a childhood onset (27-29). Pathogenic mutations in HTRA1 can manifest as the rare recessive disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), or a more frequent autosomal dominant cSVD through a loss-offunction or haploinsufficiency mechanism, respectively $(10,11)$$(10,11)$(10,11)(10,11). Notably, two different classes of pathogenic mutations have been identified in collagen type IV, producing radically different effects on collagen type IV expression and very different clinical presentations. Glycine-altering COL4A1/A2 variants produced by glycine substitutions within the triple-helical collagenous domain of COL4A1 or COL4A2 impair collagen IV folding and secretion into the basement membrane and manifest predominantly as sponta-
近年来，与cSVDs相关的基因数量不断增加（8-18）。值得注意的是，四个基因的突变——NOTCH3、HTRA1（高温要求A丝氨酸蛋白酶1）、COL4A1（IV型胶原蛋白 $\alpha 1$$\alpha 1$alpha1\alpha 1 ）和COL4A2——占成人发病单基因型cSVDs的绝大多数（表1）（19-22）。在这些单基因形式中，由NOTCH3蛋白细胞外域34个EGF重复序列中一个半胱氨酸残基的显性错义突变引起的脑常染色体显性动脉病伴皮质下梗死和白质脑病（CADASIL），是最常见的（23）。NOTCH3是一种跨膜受体，主要表达于小血管的壁细胞（平滑肌细胞（SMCs）和周细胞）。CADASIL突变典型地导致NOTCH3及其他细胞外基质（ECM）蛋白在壁细胞周围异常聚集和沉积，并通过获得性功能机制引发病理变化（24-26）。值得注意的是，NOTCH3的隐性功能丧失突变与一种罕见且严重的儿童发病型cSVD相关（27-29）。HTRA1基因的致病性突变可表现为罕见的隐性疾病——脑常染色体隐性动脉病伴皮质下梗死和白质脑病（CARASIL），或通过功能丧失或杂合不足机制导致更常见的常染色体显性cSVD。值得注意的是，在IV型胶原蛋白中已鉴定出两类不同的致病突变，这些突变对IV型胶原蛋白的表达产生根本性影响，并导致截然不同的临床表现。甘氨酸替换突变导致的COL4A1/A2基因变异，这些变异通过在COL4A1或COL4A2基因的三重螺旋胶原结构域内替换甘氨酸，会破坏胶原IV的折叠和分泌至基底膜，并主要表现为自发性...
neous ICH in deep brain regions (30). In contrast, mutations within the 3’-untranslated region of COL4A1 disrupt the binding site of the microRNA miR-29, resulting in increased COL4A1 expression. This in turn causes pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL), an cSVD characterized by ischemic lesions (14).
内源性脑内出血（ICH）发生于大脑深部区域（30）。相反，COL4A1基因3’非翻译区内的突变会破坏微RNA miR-29的结合位点，导致COL4A1表达增加。这进而引发桥脑常染色体显性微血管病伴白质脑病（PADMAL），一种以缺血性病变为特征的cSVD（14）。

Although monogenic cSVDs are thought to account for a small proportion ( $\sim 5\mathrm{\%}$$\sim 5\mathrm{\%}$∼5%\sim 5 \% ) of cSVDs, variants in NOTCH3, COL4A1/A2, and HTRA1 genes identical to those that cause monogenic cSVDs were recently found to be present at an unexpectedly high frequency in the general population and shown to increase the risk of stroke or dementia, with an additive interaction between cardiovascular risk factor burden and carrier status (Table 2) (31-39). The reason variants in these genes are associated with so broad a phenotypic spectrum is not yet fully understood. Nevertheless, for NOTCH3 and COL4A1/A2, there is emerging evidence that the position of variants affects the penetrance and expressivity of disease manifestations (40-42). Furthermore, common variants near or in NOTCH3, HTRA1, or COL4A1/A2 loci have been shown to be associated with cSVD features (Table 3) (8, 39, 43-51). In summary, these studies highlight a striking continuum between monogenic and multifactorial cSVDs. From an experimental perspective, these findings support the validity of genetically engineered animals carrying Notch3, Col4a1, Col4a2, or Htra1 pathogenic variants as clinically relevant cSVD models.
尽管单基因性cSVDs被认为仅占cSVDs的一小部分（ $\sim 5\mathrm{\%}$$\sim 5\mathrm{\%}$∼5%\sim 5 \% ），但NOTCH3、COL4A1/A2和HTRA1基因的变异与导致单基因cSVDs的变异相同，最近在普通人群中以意想不到的高频率被发现，并被证明会增加中风或痴呆的风险，且心血管危险因素负担与携带状态之间存在加性相互作用（表2）（31-39）。这些基因的变异与如此广泛的表型谱相关的原因尚不完全清楚。然而，对于NOTCH3和COL4A1/A2，有越来越多的证据表明，变异的位置会影响疾病表现的穿透率和表达程度（40-42）。此外，位于NOTCH3、HTRA1或COL4A1/A2基因座附近或内的常见变异已被证明与cSVD特征相关（表3）（8, 39, 43-51）综上所述，这些研究揭示了单基因型和多因素型cSVD之间存在显著的连续性。从实验角度来看，这些发现支持了携带Notch3、Col4a1、Col4a2或Htra1致病变异的遗传工程动物作为临床相关cSVD模型的有效性。

Establishing the nature of structural and functional changes in brain vessels in cSVDs and the sequence and timeline linking these changes to brain lesions and clinical symptoms is fundamental to understanding the pathobiology of these complex diseases. Combining the complementary information gained from studies in patients and clinically relevant mouse models of cSVD is a powerful approach for illuminating these mechanisms.
明确脑血管在cSVD中的结构和功能变化性质，以及这些变化与脑损伤和临床症状之间的时间顺序和时间线，对于理解这些复杂疾病的病理生物学至关重要。将来自患者研究和临床相关cSVD小鼠模型中获得的互补信息相结合，是一种揭示这些机制的有力方法。

Brain arteriolosclerosis, a hallmark of cSVDs, affects small parenchymal arteries and arterioles and is defined by the degeneration and loss of SMCs, the concentric fibrohyalinotic (glassy-looking acellular) thickening of the arterial wall, the accumulation of ECM components, and subsequent narrowing of the lumen (52, 53). Arteriolosclerosis is highly prevalent in autopsy specimens from individuals over 70 years old, and its severity is significantly associated with the odds of lacunes, subcortical microinfarcts, and WM degeneration (54-56). Arteriole thrombosis and obliteration are only occasionally detected, although they are likely the cause of lacunar stroke (57). Arterial pathology is qualitatively similar between sporadic and hereditary cSVDs, but is quantitatively more aggressive in hereditary forms. In particular, degeneration and loss of arteriolar SMCs is especially severe in CADASIL and CARASIL patients (53). Although pericyte coverage was not specifically examined, a recent study reported a significant reduction
脑动脉硬化是cSVDs的特征性表现，主要影响小脑实质动脉和动脉小支，其特征为平滑肌细胞（SMCs）的退化和丧失、动脉壁呈同心环状纤维玻璃样变性（无细胞的玻璃样变性）、基质成分的积聚以及随后管腔狭窄（52, 53）。动脉硬化在70岁以上个体尸检标本中高度普遍，其严重程度与腔隙、皮质下微梗死及白质变性的发生风险显著相关（54-56）。动脉小动脉血栓形成和闭塞仅偶尔被检测到，但很可能是腔隙性脑卒中的病因（57）。动脉病理在散发性和遗传性cSVD中定性相似，但在遗传性形式中定量更严重。特别是，CADASIL和CARASIL患者的动脉小血管平滑肌细胞退化和丢失尤为严重（53）。尽管未专门研究周细胞覆盖，但最近一项研究报道了显著减少

Table 1. List of genes mutated in monogenic forms of adult-onset cSVD and their prevalence
表1. 成人发病型单基因性cSVD中突变基因列表及其患病率

in the number of capillary pericytes in the frontal deep WM, a region most frequently afflicted by cSVD, in postmortem tissues from patients with vascular dementia (58). Cerebral venules, which are often overlooked, can also display collagenosis (thickening of the walls with collagen), which has been associated with WM lesions $(55,56)$$(55,56)$(55,56)(55,56).
在血管性痴呆患者的尸检组织中，额叶深层白质（WM）区域（该区域最常受cSVD影响）的毛细血管周细胞数量显著增加（58）。常被忽视的脑静脉小支也可能出现胶原病变（血管壁增厚伴胶原沉积），该病变与白质病变相关 $(55,56)$$(55,56)$(55,56)(55,56) 。

Brain arteries of aged rodents exhibit increased tortuosity (59-61). Age-related focal loss and degeneration of arterial SMCs can be detected in the superficial vascular network of the retina, a developmental extension of the brain that enables robust quantification at cellular resolution thanks to its stereotypical and planar angioarchitecture (62). Extensive, early loss of arterial SMCs is a feature of brains and retinas of mice completely lacking Notch3, a model of a very severe form of human cSVD (63-65). Interestingly, a recent study suggested that age-related arterial SMC loss might be attributable to a decline in NOTCH3 signaling (66). The cerebroretinal vasculature of Col4a1-mutant mice expressing heterozygous missense mutations that substitute critical glycine residues (G498V, G1064D, or G1344D) within the triple helical domain of COL4A1 also exhibits arterial SMC loss (65, 67, 68). Patients and mice with COL4A1 glycine-altering variants develop spontaneous ICHs in deep brain regions; importantly, pathological analyses of mutant mice indicate that ICHs originate from arteries with reduced SMC coverage, and demonstrate
老年啮齿类动物的脑动脉呈现出扭曲程度增加的特征（59-61）。在视网膜的浅表血管网络中，可检测到与年龄相关的局灶性平滑肌细胞（SMCs）丢失和退化。视网膜作为大脑的发育延伸，其典型的平面血管结构使得在细胞分辨率下进行定量分析成为可能（62）。完全缺乏Notch3的小鼠大脑和视网膜中，动脉平滑肌细胞的广泛早期丢失是其特征，这是一种非常严重的人类cSVD模型（63-65）。有趣的是，最近一项研究提示，年龄相关的动脉平滑肌细胞丢失可能与NOTCH3信号传导的下降有关（66）。表达COL4A1基因异源性错义突变（替换关键甘氨酸残基G498V、G1064D或G1344D）的小鼠脑视网膜血管也表现出动脉SMC丢失（65, 67, 68）。携带COL4A1甘氨酸替换变异的患者和小鼠在深脑区域发生自发性ICH；重要的是，对突变小鼠的病理分析表明，ICH起源于平滑肌细胞覆盖减少的动脉，并证实了这一发现。
a strong correlation between ICH burden and the severity of arterial SMC loss (67). In contrast, spontaneous ICH is not observed in patients and mice completely lacking NOTCH3 protein, suggesting that loss of arterial SMCs is necessary but not sufficient to cause ICH (65). A major difference in vascular structural integrity between Notch3-KO and Col4a1-mutant mice resides at the level of the arteriole-capillary transition (ACT) zone that lacks an elastic lamina and is surrounded by contractile mural cells that possess more irregular ensheathing processes and a more rounded nucleus than SMCs (Figure 2) (65, 69-72). Here, Notch3-KO mice exhibit a loss of mural cells, whereas Col4a1-mutant mice show an increased number of mural cells in this zone with higher contractile protein content, a defect called “hypermuscularization.” Further genetic, functional, and computational modeling studies in Col4a1-mutant mice provided evidence that arteriole SMC loss and hypermuscularization of the ACT zone act as mutually reinforcing vascular defects to cause ICH, with the excessive ACT zone muscularization raising intravascular pressure in the upstream feeding arteriole and promoting arteriolar rupture at the site of SMC loss (Figure 3) (65). Molecular studies in Col4a1-mutant mice suggest that arterial SMC loss is driven by increased TGF- $\beta$$\beta$beta\beta activity, whereas the hypermuscularization of the ACT zone arises from increased NOTCH3 activity (65, 68). Regarding the capillary bed, 2D and 3D imaging in rodents
脑内出血（ICH）负担与动脉平滑肌细胞（SMC）丢失的严重程度之间存在显著相关性（67）。然而，在完全缺乏NOTCH3蛋白的患者和小鼠中未观察到自发性ICH，这表明动脉SMC的丢失是导致ICH的必要条件但非充分条件（65）。Notch3基因敲除小鼠与Col4a1突变小鼠在血管结构完整性上的主要差异在于动脉小动脉-毛细血管过渡区（ACT区），该区域缺乏弹性层，并被具有更不规则包被突起和更圆形核的收缩性壁细胞包围（图2）（65, 69-72）。在此区域，Notch3基因敲除小鼠出现壁细胞缺失，而Col4a1突变小鼠则表现为壁细胞数量增加，且收缩蛋白含量升高，这一缺陷被称为“超肌化”。进一步的遗传学、功能学和计算建模研究在Col4a1突变小鼠中证实，动脉小动脉SMC丢失与ACT区超肌化作为相互强化血管缺陷共同导致ICH，其中ACT区过度肌化导致上游供血动脉小动脉内血管压力升高，进而促进SMC丢失部位的动脉小动脉破裂（图3）（65）。分子研究表明，Col4a1突变小鼠的动脉SMC丢失由TGF-β活性增强驱动，而ACT区过度肌化则源于NOTCH3活性升高（65, 68）。关于毛细血管床，啮齿类动物的2D和3D成像显示

Table 2. Pathogenic variants in NOTCH3, COL4A1/A2, and HTRA1 genes can lead to rare monogenic cSVD or increase the risk of stroke and dementia in the general population
表2. NOTCH3、COL4A1/A2和HTRA1基因中的致病性变异可能导致罕见的单基因cSVD，或增加普通人群中中风和痴呆的风险。

cSVD, cerebral small vessel disease; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; EGFr, epidermal growth factor-like repeat; OR, odds ratio; HR, hazard ratio.
cSVD，脑小血管病；CADASIL，脑常染色体显性动脉病伴皮质下梗死和白质脑病；CARASIL，脑常染色体隐性动脉病伴皮质下梗死和白质脑病；EGFr，表皮生长因子样重复序列；OR，比值比；HR，危险比。
revealed a small reduction in vascular length, branching density, and pericyte number, particularly in deep cortical layers and WM, in aged brains (59, 60). Pericyte coverage is reduced in Htra1-KO mice but, in striking contrast, pericyte density and/or coverage are preserved in Notch3-KO mice, Col4a1-mutant mice, and mice carrying an Arg169Cys mutation in NOTCH3 (hereafter referred to as CADASIL mice) (64, 67, 73, 74).
研究发现，衰老大脑（59, 60）中血管长度、分支密度和周细胞数量均有轻微减少，尤其在深层皮层和白质中更为显著。周细胞覆盖率在Htra1基因敲除小鼠中降低，但令人惊讶的是，周细胞密度和/或覆盖率在Notch3基因敲除小鼠、Col4a1基因突变小鼠以及携带NOTCH3基因Arg169Cys突变的小鼠（以下简称CADASIL小鼠）中得以保留（64, 67, 73, 74）。

In summary, pathological changes can affect all microvascular compartments. Remarkably, however, structural defects can differ from one microvascular segment to another for a given cSVD and can differ between cSVDs for a given microvascular compart-
综上所述，病理变化可影响所有微血管室。值得注意的是，对于同一cSVD，不同微血管段的结构缺陷可能存在差异，而对于同一微血管室，不同cSVD之间的结构缺陷也可能存在差异。
ment. Loss and degeneration of arterial SMCs, which is often overlooked, is a key feature of cSVDs and not just an end-stage lesion. Loss of SMCs is especially prominent in severe cSVDs, suggesting that it is likely an important contributing mechanism.
动脉平滑肌细胞（SMCs）的丢失和退化，这一常被忽视的现象，是cSVDs的关键特征，而不仅仅是晚期病变。在严重cSVDs中，SMCs的丢失尤为显著，这表明它很可能是重要的致病机制之一。

Arteriolosclerosis is hypothesized to stiffen the arterial wall and reduce the ability of arteries to dilate. Using ultra-high-field (7T) quantitative flow MRI, two small case-control studies showed an increased pulsatility index in perforating arteries of the basal ganglia and the WM beneath the cortex in patients with sporadic cSVD
动脉硬化被认为会使动脉壁变硬并降低动脉的舒张能力。通过使用超高压场（7T）定量血流MRI，两项小型病例对照研究发现，在散发性小血管病变（cSVD）患者中，基底节区穿通动脉及皮层下白质（WM）的脉动指数升高。

Table 3. Association between common variants (minor allele frequency >5%) in or near NOTCH3, COL4A1/A2, or HTRA1 loci and cSVD features
表3. NOTCH3、COL4A1/A2 或 HTRA1 基因位点（或其附近）常见变异（小等位基因频率 >5%）与 cSVD 特征之间的关联

A

B
CBF autoregulation  CBF 自主调节
Neurovascular coupling  神经血管耦合

Blood brain barrier Glymphatic system
血脑屏障 淋巴系统

Retrograde signal propagation
逆向信号传播
Neural activity  神经活动
Influx transporters and efflux pumps MFSD2A
内流转运蛋白和外流泵 MFSD2A

Figure 2. Integrated representation of the anatomy, cellular composition, and physiology of brain vessels. (A) Schematic of the arteriovenous axis with the four main vascular compartments, including the artery/arteriole, the arteriole-capillary transition (ACT) zone, the capillary bed and the venule/vein, and their associated cells: arterial endothelial cells (aECs), arterial SMCs (aSMCs), transitional cells (trans cells, orange), capillary endothelial cells (capECs), venous endothelial cells (vECs), and venous SMCs (vSMCs). Penetrating arteries and arterioles are separated from the brain parenchyma by a fluid-filled space (light green) that disappears as arterioles morph into capillaries and then reappears around veins. The perivascular space (inset) contains resident cells (PVMs and perivascular fibroblasts, PVFBs) and is delimited on the parenchymal side by the glia limitans formed by astrocytic endfeet. (B) Simplified depiction of the main brain vessel functions with respect to each vascular compartment. From top to bottom: (i) CBF autoregulation increases or decreases vessel diameter in response to BP decreases and increases, respectively. aSMCs are the primary sensors of BP changes and the primary effector cells driving changes in vessel diameter. (ii) Neurovascular coupling starts with the increase in local neural activity that leads to capEC hyperpolarization. Hyperpolarizing signal is propagated to upstream arterioles/arteries and transmitted to aSMCs, resulting in retrograde vasodilation. (iii) The BBB is formed by ECs, mural cells with their basement membrane, and astrocytic endfeet. Tight junctions between ECs prevent free paracellular transport of molecules; ECs express specific influx transporters and efflux pumps, which drive the active transport of specific solutes and metabolites into or out of the brain, respectively, and are enriched for the lipid transporter MFSD2A, which inhibits the rate of transcytosis $(113,166)$$(113,166)$(113,166)(113,166). (iv) The glymphatic system involves (a) CSF influx along the periarterial spaces, driven mainly by arterial pulsatility; (b) CSF entry into the brain supported by aquaporin 4 (AQP4) channel expression on the astrocytic endfeet, subsequent mix with the ISF, and flow through the extracellular spaces; and © the efflux of extracellular fluid and wastes along perivenous spaces.
图2. 大脑血管的解剖结构、细胞组成及生理功能的综合示意图。(A) 动静脉轴的示意图，包括四个主要血管腔室：动脉/动脉小支、动脉小支-毛细血管过渡区（ACT区）、毛细血管床和静脉小支/静脉，以及与其相关的细胞：动脉内皮细胞（aECs）、动脉平滑肌细胞（aSMCs）、过渡细胞（trans cells，橙色），毛细血管内皮细胞（capECs）、静脉内皮细胞（vECs）和静脉平滑肌细胞（vSMCs）。穿透性动脉和动脉小支通过充满液体的空间（浅绿色）与脑实质分离，该空间在动脉小支转化为毛细血管时消失，随后在静脉周围重新出现。血管周围空间（插图）含有驻留细胞（PVMs 和血管周围成纤维细胞，PVFBs），并由星形胶质细胞的终末突起形成的胶质限制层在实质侧界定。(B) 脑血管各室功能的简化示意图。自上而下： (i) 脑血流自动调节（CBF）根据血压（BP）的升高或降低相应增大或减小血管直径。aSMCs是血压变化的主要感受器，也是驱动血管直径变化的主要效应细胞。 (ii) 神经血管耦合始于局部神经活动增强导致毛细血管内皮细胞（capEC）超极化。超极化信号向上游动脉/动脉传播并传递至aSMCs，导致逆行性血管舒张。 (iii) 血脑屏障由ECs、具有基底膜的壁细胞和星形胶质细胞的终末突起构成。 紧密连接阻止了细胞间隙的自由旁路运输；内皮细胞（ECs）表达特异性内流转运蛋白和外排泵，分别驱动特定溶质和代谢物的主动运输进入或离开大脑，且富含脂质转运蛋白MFSD2A，该蛋白抑制转胞吞作用的速率 $(113,166)$$(113,166)$(113,166)(113,166) 。(iv) 脑脊液淋巴系统包括：(a) 脑脊液沿动脉周围间隙流入，主要由动脉搏动驱动；(b) 脑脊液通过星形胶质细胞足突上表达的水通道蛋白4（AQP4）通道进入脑组织，随后与间质液混合并通过细胞外间隙流动；以及 (c) 细胞外液和废物沿静脉周围间隙外排。

Figure 3. Opposite changes in mural cells in the arteriole-capillary transition zone are associated with distinct cSVD features. Schematic representation of brain vessels in (A) the collagen IV-related cSVD, which manifests as recurrent spontaneous ICHs, and in (B) the NOTCH3 null-driven cSVD, which is characterized by recurrent deep infarcts. (A) In the collagen IV disease, the ACT zone shows an increased number of mural cells with higher contractile protein content, raising intravascular pressure in the upstream feeding arteriole, which exhibits loss of SMCs, and promoting arteriolar rupture at the site of SMC loss and hemorrhage (red). (B) In the NOTCH3 null-driven cSVD, the combination of loss of arterial SMCs and loss of mural cells in the ACT zone is predicted to decrease perfusion pressure and promote ischemic lesions in the deep brain regions (gray).
图3. 动脉小球毛细血管过渡区壁细胞的相反变化与不同的cSVD特征相关。图示了（A）与IV型胶原相关的cSVD（表现为反复发作的自发性脑内出血）和（B）NOTCH3基因缺失驱动的cSVD（以反复发作的深部梗死为特征）中的脑血管结构。(A) 在胶原IV疾病中，ACT区壁细胞数量增加且收缩蛋白含量升高，导致上游供血动脉的血管内压力升高，该动脉平滑肌细胞（SMCs）丢失，进而促进SMCs丢失部位的动脉破裂和出血（红色）。(B) 在NOTCH3缺失驱动的cSVD中，动脉SMCs和ACT区壁细胞的双重缺失预计会降低灌注压力，促进深脑区域（灰色）的缺血性病变。
or CADASIL compared with controls, suggestive of increased arterial stiffness (75, 76). Hypercapnia, likely through effects on both endothelial cells and SMCs, is a potent vasodilatory stimulus that is commonly used in clinics to assess the capacity of cerebral vessels to dilate (77). ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2}-induced vasodilation is assessed by measuring cerebral blood flow (CBF) increases in response to breathing ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2} with functional MRI using blood ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} level-dependent (BOLD) response or arterial spin labeling, which can directly measure CBF. Two recent, large cross-sectional cohort studies showed that a reduced ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2} response in the WM or subcortical gray matter is associated with more severe cSVD burden (WMHs, lacunes, microbleeds, enlarged PVSs, and brain atrophy) and impaired cognition (78, 79). In a 1-year longitudinal study performed in patients with age-related WMHs, regions of normal-appearing WM that progress to WMHs over time had a lower baseline response to hypercapnia compared with normal-appearing WM (80).
与对照组相比，CADASIL患者的动脉僵硬度增加（75, 76），提示动脉僵硬度升高。高碳酸血症通过作用于内皮细胞和平滑肌细胞，是一种强大的血管舒张刺激，常用于临床评估脑血管的舒张能力（77）。 ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2} 诱导的血管舒张通过测量呼吸 ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2} 后脑血流（CBF）的增加来评估，采用功能性磁共振成像（fMRI）结合血氧水平依赖（BOLD）信号或动脉自旋标记技术，后者可直接测量CBF。两项近期的大型横断面队列研究显示，白质（WM）或皮层下灰质中 ${\mathrm{CO}}_2$${\mathrm{CO}}_2$CO_(2)\mathrm{CO}_{2} 反应降低与更严重的cSVD负担（WMHs、 lacunes、微出血、扩大PVs及脑萎缩）及认知功能障碍相关（78, 79）。在一项针对年龄相关性WMHs患者的1年纵向研究中，随时间进展为WMHs的正常外观WM区域，其基线对高碳酸血症的反应低于正常外观WM（80）。

In pharmacological and genetic models of hypertension, cross-sectional area and wall thickness are generally increased, which is considered an adaptive response to increased intravascular pressure that serves to reduce wall stress (81). These changes are associated with stiffening of large pial arteries, but increased distensibility of small pial arterioles. They also occur rapidly (within $\sim 1$$\sim 1$∼1\sim 1 week) after the development of hypertension and can recover with blood pressure (BP) normalization (82). In angiotensin II-induced (AngII-induced) hypertensive models, a reduction in lumen diameter (inward remodeling) also develops slowly (over weeks) and does not recover with BP normalization (82). Inward remodeling is considered a maladaptive response to hypertension that is predicted to profoundly reduce CBF. Strikingly, pial arteries of CADASIL mice also exhibit inward remodeling, despite the fact that these mice are normotensive. This defect occurs very early, prior to any other functional changes (83, 84). Furthermore, Htra1-KO mice develop age-dependent
在药理学和遗传学高血压模型中，横截面积和壁厚度通常增加，这被认为是适应性反应，旨在通过减少壁应力来应对血管内压力的升高（81）。这些变化与大皮层动脉的僵硬化相关，但小皮层动脉的顺应性增加。这些变化发生迅速（在高血压发展后 $\sim 1$$\sim 1$∼1\sim 1 周内），且可在血压（BP）正常化后恢复（82）。在血管紧张素II诱导（AngII诱导）的高血压模型中，管腔直径减小（内向重塑）也缓慢发展（数周内），且不会随BP正常化而恢复（82）。向内重塑被认为是高血压的不适应性反应，预计会显著降低脑血流（CBF）。值得注意的是，CADASIL小鼠的脑膜动脉也表现出向内重塑，尽管这些小鼠血压正常。这种缺陷发生得非常早，早于其他任何功能性改变（83, 84）。此外，Htra1基因敲除（KO）小鼠会出现年龄依赖性
accumulation of matrisome proteins, abnormal internal elastica lamina, and decreased distensibility at the level of pial arteries, again in the context of normal BP (74).
脑膜蛋白的积累、异常的弹性纤维层以及脑膜动脉水平的伸展性降低，这些变化均发生在血压正常的背景下（74）。

In summary, vessel wall remodeling and stiffening of large brain arteries appears to be a consistent feature across cSVDs, and these defects can occur very early in the disease process, even in a context of normal BP. Studies in patients suggest that the reduced capacity of brain vessels to dilate precedes the appearance of WMHs, one of the earliest types of damage in the brain parenchyma of cSVD patients. Moreover, this reduced dilatory capacity is correlated with the severity of cSVD brain lesions and thus may functionally contribute to them.
综上所述，大脑动脉血管壁重塑和僵硬似乎是cSVDs中的一致特征，且这些缺陷可能在疾病早期阶段就已出现，即使在血压正常的背景下也是如此。患者研究表明，脑血管扩张能力的减退先于脑白质高信号（WMHs）的出现，而WMHs是cSVD患者脑实质中最早出现的损伤类型之一。此外，这种扩张能力减退与cSVD脑损伤的严重程度相关，因此可能在功能上对损伤的发生起到促进作用。

Autoregulation maintains relatively stable CBF in the face of moment-to-moment fluctuations in arterial BP. SMCs of arteries and arterioles are the primary sensors of changes in BP and the primary effector cells that drive intravascular pressure-dependent changes in diameter, increasing or decreasing vessel diameter in response to BP decreases and increases, respectively (Figure 2B) (85).
自主调节在动脉血压（BP）的瞬时波动下维持脑血流（CBF）的相对稳定。动脉和小动脉的平滑肌细胞（SMCs）是血压变化的主要感受器，也是驱动血管内压力依赖性直径变化的主要效应细胞，其通过增加或减少血管直径来响应血压的降低或升高（图2B）（85）。

Dynamic CBF autoregulation (dCA) can be assessed in humans by quantifying how spontaneous fluctuations in BP are transferred to CBF from simultaneous recording of BP and CBF velocity using transcranial Doppler (85). A recent case-control study ( $n=113$$n=113$n=113n=113 cSVD patients and 83 controls) showed that dCA was altered bilaterally in patients and that the degree of impairment was positively associated with the burden of cSVD MRI markers (86).
动态脑血流自调节（dCA）可通过定量分析血压（BP）的自发波动如何传递至脑血流（CBF），从而在人类中进行评估。该评估基于同时记录的血压和脑血流速度数据，采用经颅多普勒成像技术（85）。一项近期病例对照研究（ $n=113$$n=113$n=113n=113 cSVD患者和83名对照）显示，患者双侧dCA发生改变，且功能障碍程度与cSVD MRI标志物的负担呈正相关（86）。

Experimental studies have shown that pressure-induced constriction (myogenic tone) and CBF autoregulation are impaired in hypertensive mice and in several models of monogenic cSVD. In young hypertensive mice, pial arteries exhibit increased myogenic tone and the autoregulation curve is right-shifted toward higher BP. However, this increase in myogenic constriction, which
实验研究表明，压力诱导的血管收缩（肌源性张力）和脑血流自动调节在高血压小鼠及多种单基因性小血管病变（cSVD）模型中均受损。在年轻高血压小鼠中，脑膜动脉表现出肌源性张力增高，且自动调节曲线向较高血压方向右移。然而，这种肌源性收缩的增加，
is thought to protect the distal portion of the vascular network from pressure overload, is lost in aged hypertensive mice (87). In mice carrying a G1344D or G394V glycine mutation in Col4a1, pial arteries exhibit an age-dependent reduction in myogenic tone caused by decreased activity of transient receptor potential melastatin 4 (TRPM4) channels, which are positive regulators of arterial tone (88, 89). Myogenic tone in Col4a1-mutant mice can be restored by improving COL4A1-COL4A2 trafficking using the chemical chaperone 4-phenylbutyrate (88). Interestingly, restoration of myogenic tone is associated with a reduction in the occurrence of ICH, an observation concordant with the current view that myogenic tone protects the vascular bed from pressure overload and ICH (88). In pial arteries of Notch3-KO mice, which exhibit arterial SMC loss, myogenic tone is strongly reduced and CBF autoregulation is severely compromised, with extreme narrowing of the autoregulated range (63, 90). In CADASIL mice, myogenic tone is reduced in pial arteries and penetrating arteries in the absence of overt SMC loss, and the lower limit of CBF autoregulation is right-shifted toward higher BP (83, 91). Decreased myogenic tone and impaired CBF autoregulation in CADASIL mice are attributable to the pathological accumulation of tissue inhibitor of metalloproteinase 3 (TIMP3) protein in NOTCH3 ${}^{\text{ECD}}$${}^{\text{ECD }}$^("ECD "){ }^{\text {ECD }} deposits that results in increased density of voltage-gated potassium $\left({\mathrm{K}}^{+}\right)\left({\mathrm{K}}_{\mathrm{v}}\right)$$\left({\mathrm{K}}^{+}\right)\left({\mathrm{K}}_{\mathrm{v}}\right)$(K^(+))(K_(v))\left(\mathrm{K}^{+}\right)\left(\mathrm{K}_{\mathrm{v}}\right) channels, which are powerful negative regulators of arterial tone, in arterial SMCs $(92,93)$$(92,93)$(92,93)(92,93).
被认为能保护血管网络的远端部分免受压力过载，但在老年高血压小鼠中丢失（87）。在携带Col4a1基因G1344D或G394V甘氨酸突变的小鼠中，脑膜动脉表现出随年龄增长而减少的肌源性张力，这归因于瞬时受体电位通道4（TRPM4）活性降低，而TRPM4是动脉张力的正调节因子（88, 89）。通过使用化学伴侣4-苯基丁酸改善COL4A1-COL4A2的转运，可恢复Col4a1突变小鼠的肌源性张力（88）。有趣的是，肌源性张力的恢复与颅内出血（ICH）发生率的降低相关，这一观察结果与当前认为肌源性张力可保护血管床免受压力过载和ICH损害的观点一致（88）。在Notch3基因敲除小鼠的脑膜动脉中，由于平滑肌细胞丢失，肌源性张力显著降低，脑血流自动调节功能严重受损，自动调节范围极度缩窄（63, 90）。在CADASIL小鼠中，皮层动脉和穿通动脉的肌源性张力降低，且未伴随明显的平滑肌细胞丢失，CBF自动调节的下限向更高血压方向右移（83, 91）。CADASIL小鼠中肌源性张力降低和CBF自主调节功能障碍归因于NOTCH3 ${}^{\text{ECD}}$${}^{\text{ECD }}$^("ECD "){ }^{\text {ECD }} 沉积物中金属蛋白酶抑制剂3（TIMP3）蛋白的病理性积累，这导致动脉SMC中电压门控钾通道密度增加，而这些通道是动脉张力的强大负调节因子。

In summary, there is some evidence that CBF autoregulation is compromised in patients and experimental models with cSVD, although the intrinsic mechanism - increased or decreased myogenic tone, loss or dysfunction of arterial SMCs - appears to differ among diseases. A key unanswered question is whether a rightward shift in the lower limit of CBF autoregulation to higher BP actually renders the brain, particularly its deep regions, more sensitive to low BP and its potential ischemic consequences.
综上所述，现有证据表明，在cSVD患者及实验模型中，脑血流（CBF）的自主调节功能存在异常，尽管其内在机制（如肌源性张力增高或降低、动脉平滑肌细胞（SMCs）的丢失或功能障碍）在不同疾病中可能存在差异。一个关键的未解问题是，CBF自主调节下限向更高血压（BP）方向的右移，是否确实使大脑（尤其是其深层区域）对低血压及其潜在缺血性后果更为敏感。

Considering that WM receives its blood supply from the distal end of long medullary arteries (94), that WM lesions first start in brain areas that are furthest from the origin of the perforating arteries, and that brain arteriolosclerosis is characterized by stenosis of these arteries, it has long been thought that cSVD-related WM lesions are caused by chronic hypoperfusion. Consistent with this idea is the seminal observation of WM rarefaction in a mouse model of chronic hypoperfusion induced by bilateral common carotid artery stenosis (95). Numerous studies have explored the relationship between resting CBF and WMHs at the cross-sectional level. A recent meta-analysis including 2,180 participants from 34 studies showed that WMH burden in patients was worse and CBF was lower in regions with WMHs than in regions with normal-appearing WM. However, the few available longitudinal studies have yielded contradictory results (96); thus, whether reduction in resting CBF precedes or follows WMH progression remains in dispute. Concurrent measurement of the ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} extraction fraction (OEF), which can now be quantified using noninvasive MRI-based techniques, may be a promising approach for disentangling whether hypoperfusion is a cause or consequence of WMHs, since low CBF and elevated OEF are signatures of hypoxia/ischemia, whereas low CBF and low OEF indicate matched low ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} supply and demand (97).
考虑到白质（WM）的血液供应来自长髓质动脉的远端（94），WM病变首先出现在距离穿通动脉起源最远的大脑区域，且脑动脉硬化以这些动脉的狭窄为特征，长期以来认为cSVD相关的WM病变是由慢性缺血引起的。与这一观点一致的是，在双侧颈总动脉狭窄引起的慢性缺血小鼠模型中，观察到WM稀疏化的经典现象（95）。大量研究探讨了静息状态下脑血流（CBF）与WM病变（WMHs）在横断面水平的关系。一项纳入34项研究、共2180名参与者的荟萃分析显示，患者脑白质病变负担更重且CBF更低的区域，其脑白质病变比正常外观脑白质区域更严重。然而，少数纵向研究结果相互矛盾（96）；因此，静息状态下CBF降低是脑白质病变进展的先兆还是后果，仍存在争议。同时测量 ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} 提取分数（OEF）可能是一种有前景的方法，以厘清低灌注是WMHs的成因还是后果。这是因为低CBF和升高的OEF是缺氧/缺血的标志，而低CBF和低OEF则表明 ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} 供需匹配(97)。

Widespread reduction in resting CBF has been reported in Notch3-KO, CADASIL, and Htra1-KO mice, although the mechanism(s) are not fully understood (66, 74, 83). Interestingly, treatment with an AngII receptor type 1 (AT1) blocker improved CBF in Htra1KO mice in association with reduced accumulation of matrisome proteins and amelioration of pial artery distensibility defects.
研究发现，Notch3基因敲除（Notch3-KO）、CADASIL和Htra1基因敲除（Htra1-KO）小鼠的静息脑血流（CBF）普遍减少，但其机制尚不完全清楚（66, 74, 83）。值得注意的是，使用血管紧张素II受体1型（AT1）拮抗剂治疗后，Htra1KO小鼠的CBF得到改善，同时伴随基质蛋白积累减少及脑膜动脉顺应性缺陷的缓解。

In summary, whereas chronic hypoperfusion is an indisputable feature in both cSVD mouse models and patients, whether it is a cause or consequence of brain damage and whether brain hypoperfusion contributes to disease manifestations remain unclear. In humans, recently developed approaches can disentangle this “chicken and egg” question. In mouse models, an in-depth characterization of brain lesions combined with a detailed analysis of the time course of CBF changes might be informative.
综上所述，尽管慢性脑血流减少是cSVD小鼠模型和患者中无可争议的特征，但它究竟是脑损伤的原因还是后果，以及脑血流减少是否参与疾病表现的形成，目前尚不明确。在人类研究中，近期发展的新方法有望厘清这一“鸡生蛋还是蛋生鸡”的因果关系。在小鼠模型中，对脑损伤的深入特征描述结合对脑血流变化时间过程的详细分析，可能提供有价值的线索。

Neurovascular coupling (NVC) - the ensemble of mechanisms that mediate activity-dependent increases in blood perfusion (functional hyperemia) - ensures appropriate delivery of nutrients and ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} in response to changes in local neural activity. Multiple redundant pathways and molecules are involved in linking neural activity to vessel dilation. A recent new paradigm envisions the vast capillary network within the brain acting as a sensory web capable of detecting increases in neuronal activity and sending rapid signals that dilate upstream arteries. In this conceptualization, extracellular ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+}and nitric oxide (NO) are viewed as the most important neurovascular coupling mediators (98). Endothelial cells sense neural activity-derived ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+}through the inward-rectifying ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+}channel, Kir2.1, which is activated by modest elevations in extracellular ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+}(produced during each action potential), resulting in endothelial cell hyperpolarization. This hyperpolarizing signal rapidly propagates retrogradely from cell to cell through the capillary network via gap junctions, ultimately reaching upstream arterioles and pial arteries. There, the signal passes to SMCs through myoendothelial projections, dilating arteries/arterioles and increasing blood flow to the site of signal initiation (Figure 2B) (99). More distally located thin-strand pericytes have also been reported to regulate capillary blood flow, but with slower kinetics than arteriolar SMCs and mural cells of the ACT zone (100). Besides supplying the metabolic needs of active neurons, NVC may serve additional purposes, such as removing metabolic waste through a vascular route, homogenizing flow in the capillary network, preventing capillary stalls by leucocytes, regulating brain temperature, facilitating cerebrospinal fluid (CSF) movement, and stabilizing the vascular network (101).
神经血管耦合（NVC）——介导活动依赖性血流灌注增加（功能性充血）的一系列机制——确保了营养物质和 ${\mathrm{O}}_2$${\mathrm{O}}_2$O_(2)\mathrm{O}_{2} 在局部神经活动变化时得到适当输送。多个冗余通路和分子参与将神经活动与血管舒张相联系。最近提出的一个新范式认为，大脑中庞大的毛细血管网络作为一个感觉网络，能够检测神经活动增加并发送快速信号以舒张上游动脉。在此概念中，细胞外 ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+} 和一氧化氮（NO）被视为最重要的神经血管耦合介质（98）。内皮细胞通过内向整流通道Kir2.1感知神经活动诱发的 ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+} ，该通道在细胞外 ${\mathrm{K}}^{+}$${\mathrm{K}}^{+}$K^(+)\mathrm{K}^{+} （每次动作电位期间产生）轻微升高时被激活，导致内皮细胞超极化。这种超极化信号通过间隙连接在毛细血管网络中逆向快速传播，最终到达上游动脉和小脑动脉。在那里，信号通过肌内皮突触传递给平滑肌细胞，导致动脉/动脉扩张并增加信号起始部位的血流量（图2B）（99）。更远端的薄束状周细胞也被报道可调节毛细血管血流，但其动力学比动脉小动脉的平滑肌细胞和ACT区壁细胞更慢（100）。 除了满足活跃神经元的代谢需求外，NVC还可能具有其他功能，例如通过血管途径清除代谢废物、在毛细血管网络中均匀分布血流、防止白细胞导致毛细血管堵塞、调节脑温度、促进脑脊液（CSF）流动以及稳定血管网络（101）。

NVC can be assessed in humans by monitoring responses to a motor or visual stimulus using functional MRI to measure BOLD responses or through application of arterial spin labeling techniques. But despite the availability of such approaches, there are few studies on cSVD patients. Two independent case-control studies reported significant changes in NVC in CADASIL patients, demonstrating reduced amplitude or a time-shifted decrease in the hemodynamic response (75, 102). However, one caveat with human studies is that the altered blood flow response might be related to a reduction in the neural response due to brain lesions rather than a decrease in NVC efficiency originating in the vascular bed.
NVC可在人类中通过监测对运动或视觉刺激的反应来评估，具体方法包括使用功能性磁共振成像（fMRI）测量血氧水平依赖（BOLD）信号，或应用动脉自旋标记技术。然而，尽管这些方法已可用，但针对cSVD患者的研究仍寥寥无几。两项独立的病例对照研究报道了CADASIL患者中NVC的显著变化，表现为血流动力学反应的幅度降低或时间延迟性下降（75, 102）。然而，人类研究的一个局限性在于，血流反应的改变可能与脑损伤导致的神经反应减少有关，而非源于血管床的NVC效率降低。

Mouse studies have pointed to vascular rather than neural causes of NVC deficiencies. Among these, one recent report provided convincing evidence that aging-related deterioration is caused by an age-dependent decrease in vasoresponsivity that is most pronounced at precapillary sphincters (a novel structure identified in the cortex at the transition between some arterioles and the ACT zone; ref. 103), rather than caused by reduced neuronal activity (104). Hypertension also impairs NVC (105). In AngII-induced chronic hypertension, activation of AT1 receptors in perivascular macrophages (PVMs, a population of resident macrophages in the PVS) is involved in NVC deficits and leads to the production of reactive oxygen species, which impair endothelium-dependent responses (106). NVC is also disrupted in the BPH/2 mouse model of neurogenic hypertension (107). The underlying mechanisms involve PVMs, as described above, as well as defective capillary-to-arteriole signaling caused by a diminished activity of the capillary endothelial cell Kir2.1 channel (108). Strikingly, Col4a1-mutant and CADASIL mice, like hypertensive mice, exhibit an age-dependent reduction in functional hyperemia that also results from defective capillary-to-arteriole signaling as a consequence of diminished capillary endothelial cell Kir2.1 channel activity. Remarkably, the fundamental defect underlying this channelopathy (depletion of the minor membrane phospholipid phosphatidylinositol 4,5-bisphosphate ( ${\mathrm{PIP}}_2$${\mathrm{PIP}}_2$PIP_(2)\mathrm{PIP}_{2} ), a key activator of the Kir2.1 channel) is similar in Col4a1-mutant and CADASIL mice, although the intrinsic mechanisms differ (25, 88, 92, 93, 109-111). Interestingly, restoring functional hyperemia by depleting PVMs in hypertensive mice and by chronic inhibition of phosphoinositide-3-kinase (PI3K) in Col4a1-mutant mice improved memory deficits $(106,111)$$(106,111)$(106,111)(106,111). Although these findings support the hypothesis that a chronic reduction in NVC could account for cognitive deficits, further studies are needed to substantiate this relationship and rule out possible confounding effects of specific experimental maneuvers, which may have additional effects on the brain or brain vessels.
小鼠研究指出，NVC缺陷的原因在于血管而非神经。其中，一项最新研究提供了有力证据，表明与年龄相关的退化是由年龄依赖性血管反应性下降引起的，这种下降在前毛细血管括约肌（一种在皮层中某些动脉和小动脉过渡到ACT区时新发现的结构；参考文献103）中最为明显，而非由神经活动减少引起（104）。高血压也会损害NVC（105）。在血管紧张素II（AngII）诱导的慢性高血压中，血管周围巨噬细胞（PVMs，PVS中的一群驻留巨噬细胞）中的AT1受体激活参与了NVC缺陷，并导致活性氧种类的产生，从而损害内皮依赖性反应（106）。NVC在神经源性高血压的小鼠模型（BPH/2）中也受到破坏（107）。其潜在机制包括上述PVMs的作用，以及由于毛细血管内皮细胞Kir2.1通道活性降低导致的毛细血管至动脉信号传导缺陷（108）。值得注意的是，Col4a1突变小鼠和CADASIL小鼠与高血压小鼠类似，表现出随年龄增长而减少的功能性充血，这同样源于毛细血管至动脉信号传导缺陷，后者由毛细血管内皮细胞Kir2.1通道活性降低引起。值得注意的是，这种通道病变的根本缺陷（即关键激活剂——膜磷脂磷脂酰肌醇4,5-二磷酸（ ${\mathrm{PIP}}_2$${\mathrm{PIP}}_2$PIP_(2)\mathrm{PIP}_{2} ）的耗竭）在Col4a1突变和小鼠和CADASIL小鼠中相似，尽管内在机制不同（25, 88, 92, 93,109-111）。 有趣的是，通过耗竭PVMs在高血压小鼠中恢复功能性充血，以及通过慢性抑制磷脂酰肌醇-3激酶（PI3K）在Col4a1突变小鼠中，改善了记忆缺陷 $(106,111)$$(106,111)$(106,111)(106,111) 。尽管这些发现支持慢性NVC减少可能导致认知缺陷的假设，但仍需进一步研究以证实这一关联并排除特定实验操作可能带来的混杂效应，这些操作可能对大脑或脑血管产生额外影响。

In summary, deterioration of NVC is a recurrent theme in mouse models of sporadic and genetic cSVDs. Remarkably, experimental studies have identified shared mechanisms between sporadic and genetic cSVDs, pointing to dysfunction of a single endothelial cell ion channel (Kir2.1) in both cases. Studies in CADASIL patients and mouse models of CADASIL suggest that NVC is impaired prior to the development of subcortical infarcts $(93,102)$$(93,102)$(93,102)(93,102). Additional human studies are needed to assess the reproducibility of BOLD responses in cSVD patients (112) and study the timeline of NVC dysfunction with respect to the appearance of brain lesions and clinical manifestations. Further experimental studies are warranted to better understand whether and how chronic dysfunction of such an important mechanism impairs brain functioning.
综上所述，NVC的恶化是散发性和遗传性cSVD小鼠模型中的一个常见主题。值得注意的是，实验研究已识别出散发性和遗传性cSVD之间的共同机制，指出两种情况下均存在单一内皮细胞离子通道（Kir2.1）功能障碍。CADASIL患者及CADASIL小鼠模型研究表明，NVC在皮层下梗死形成前即已受损 $(93,102)$$(93,102)$(93,102)(93,102) 。需要更多人类研究来评估cSVD患者中BOLD反应的可重复性（112），并研究NVC功能障碍与脑损伤及临床表现出现的时间线。进一步的实验研究有必要以更好地理解这种重要机制的慢性功能障碍是否以及如何损害脑功能。

The blood-brain barrier (BBB) limits the movement of ions, amino acids, molecules, and cells into and out of the brain (Figure 2B) (113). The glymphatic system is a fluid-clearance pathway thought to primarily serve the function of nonselectively clearing metabolic waste from the brain interstitial space (114). This process, which is primarily active during sleep, is initiated by the flow of CSF along the PVS-surrounding arteries and its entry into the brain. CSF mixes with the interstitial fluid (ISF) in the parenchy-
血脑屏障（BBB）限制了离子、氨基酸、分子和细胞在脑内外的运动（图2B）（113）。甘淋巴系统是一种液体清除通路，被认为主要负责非选择性清除脑间质空间中的代谢废物（114）。这一过程主要在睡眠期间活跃，由脑脊液（CSF）沿脉络丛周围动脉流动并进入大脑而启动。CSF与脑实质中的间质液（ISF）混合。
ma, leaves the brain along perivenular spaces, and is ultimately exported by meningeal lymphatic vessels and along cranial and spinal nerve sheaths toward the cervical lymph nodes (Figure 2B) $(114,115)$$(114,115)$(114,115)(114,115). The flow of CSF in the spaces around pial arteries is pulsatile, reflecting dynamic changes in arterial diameter caused by cardiac impulse waves (arterial pulsatility), which are important physiological drivers that pump CSF inward along these spaces (116). Recent work has further implicated PVMs as important regulators of CSF flow dynamics through their involvement in arterial motion and remodeling of the vascular ECM (117).
脑脊液沿脑室周围的静脉周围间隙流出，最终通过脑膜淋巴管及颅神经和脊神经鞘向颈部淋巴结排出（图2B） $(114,115)$$(114,115)$(114,115)(114,115) 。脑膜动脉周围空间中的脑脊液流动呈脉动性，反映了心脏搏动波引起的动脉直径动态变化（动脉脉动性），这是推动脑脊液沿这些空间向内流动的重要生理驱动因素（116）。近期研究进一步揭示了脑膜血管（PVMs）通过参与动脉运动及血管外基质（ECM）重塑，在调节脑脊液流动动力学中发挥重要调节作用（117）。

Leakage of fibrinogen and other plasma proteins into the brain parenchyma has harmful effects that affect microglial activation, cause neuronal and axonal loss, and promote demyelination and inhibition of remyelination $(118,119)$$(118,119)$(118,119)(118,119). Moreover, this leakage can increase interstitial fluid and cause WM edema. Two studies, using diffusion MRI and a 2 -compartment model, support the possibility of increased extracellular free water in WM in patients with sporadic cSVD or CADASIL $(120,121)$$(120,121)$(120,121)(120,121). On the basis of these observations, it has been proposed that cSVD-related brain lesions (WMHs or infarcts) could arise from a leaky BBB. Alternatively, Benveniste and Nedergaard recently crafted the novel hypothesis that failure of fluid transport via the glymphatic system could cause enlargement of PVSs, accumulation of interstitial fluid in WM, and ultimately, demyelination (122).
纤维蛋白原和其他血浆蛋白渗入脑实质会产生有害作用，影响小胶质细胞活化，导致神经元和轴突损伤，并促进脱髓鞘和抑制髓鞘再生 $(118,119)$$(118,119)$(118,119)(118,119) 。此外，这种渗漏还可能增加间质液量并引发白质水肿。两项研究采用扩散MRI和两室模型，支持散发性cSVD或CADASIL患者白质中细胞外自由水增加的可能性 $(120,121)$$(120,121)$(120,121)(120,121) 。基于这些观察结果，提出cSVD相关脑损伤（白质病变或梗死）可能源于血脑屏障（BBB）通透性增加。另一方，Benveniste和Nedergaard最近提出了新假说：甘淋巴系统（glymphatic system）的液体运输功能障碍可能导致脑室周围脑室（PVSs）扩大、WM间质液积聚，最终引发脱髓鞘（122）。

BBB integrity in humans can be assessed by quantifying the dynamic extravasation (paracellular leakage) of small contrast agent molecules ( $\sim 550\mathrm{Da}$$\sim 550\mathrm{Da}$∼550Da\sim 550 \mathrm{Da} for gadolinium) into the brain parenchyma using dynamic contrast-enhanced MRI. Cross-sectional case-control studies have generally shown changes consistent with widespread, but subtle (i.e., detectable after noise filtering) BBB leakage as well as hotspots of increased BBB permeability in patients with sporadic cSVD (123-125). Cohort studies have shown an association between WMH volume and increased BBB permeability (126, 127). Moreover, longitudinal studies have identified a link between BBB leakage at baseline and the loss of microstructural integrity over time in the perilesional zones around WMHs and further showed that greater BBB leakage at baseline was associated with more severe decline in cognitive functions, especially executive function. Taken together, these data suggest that BBB impairment might play an early role in subsequent WM lesions $(128,129)$$(128,129)$(128,129)(128,129). Nonetheless, studies in CADASIL patients have produced contradictory results (125, 130). Analyzing water exchange across the BBB using arterial spin labeling MRI is another promising approach for assessing subtle BBB dysfunction since water’s molecular weight ( $\sim 18\mathrm{Da}$$\sim 18\mathrm{Da}$∼18Da\sim 18 \mathrm{Da} ) is much smaller than that of gadolinium-based contrast agents $(131,132)$$(131,132)$(131,132)(131,132). Using arterial spin labeling MRI, Yang and colleagues recently reported a diffuse alteration (in the whole brain) in the water exchange rate across the BBB in patients with CADASIL or HTRA1-related cSVD, suggestive of an increase in the BBB’s permeability to water (133). BBB integrity in the mouse is compromised upon aging (134). It has also been reported that AngII-induced hypertension enhances BBB permeability by reducing endothelial tight junctions and increasing transcytosis, mainly in arterioles and venules. The mechanism underlying this enhanced BBB permeability primarily involves cooperative interactions of AT1-expressing endothelial cells with
人类血脑屏障（BBB）的完整性可通过动态对比增强磁共振成像（dynamic contrast-enhanced MRI）定量测定小分子对比剂（如钆）的动态外渗（旁细胞漏出）进入脑实质来评估。横断面病例对照研究通常显示，散发性小血管病变（cSVD）患者存在广泛但轻微（即经过噪声滤波后可检测到）的BBB渗漏，以及BBB通透性增高的热点区域（123-125）。队列研究表明，白质高信号（WMH）体积与BBB通透性增高存在关联（126, 127）。此外，纵向研究发现基线时BBB渗漏与WMH周围病灶周围区域微结构完整性随时间丧失之间存在关联，并进一步表明基线时BBB渗漏程度越高，认知功能（尤其是执行功能）衰退越严重。综合上述数据，BBB功能障碍可能在后续WM病变中发挥早期作用 $(128,129)$$(128,129)$(128,129)(128,129) 。然而，CADASIL患者的研究结果存在矛盾（125, 130）。利用动脉自旋标记MRI分析BBB的水交换是评估BBB功能障碍的另一种有前景的方法，因为水的分子量（ $\sim 18\mathrm{Da}$$\sim 18\mathrm{Da}$∼18Da\sim 18 \mathrm{Da} ）远小于钆基对比剂 $(131,132)$$(131,132)$(131,132)(131,132) 。Yang等近期采用动脉自旋标记MRI发现，CADASIL或HTRA1相关cSVD患者全脑BBB水交换率存在弥漫性改变，提示BBB对水通透性增加（133）。小鼠BBB完整性随年龄增长而受损（134）。 有研究报道，血管紧张素II（AngII）诱导的高血压可通过减少内皮细胞紧密连接并增加转胞吞作用，增强血脑屏障（BBB）通透性，这一现象主要发生在动脉和小静脉中。这种增强的血脑屏障通透性机制主要涉及表达AT1受体的内皮细胞与

PVMs (135). In contrast, the BBB was reported to be preserved in the deoxycorticosterone acetate salt hypertensive model, as well as in adult Col4a1-mutant, CADASIL, or CARASIL mice ( $67,73,74,136$$67,73,74,136$67,73,74,13667,73,74,136 ).
PVMs（135）。相比之下，BBB在去氧皮质酮醋酸盐诱导的高血压模型中被报道为完整，同样在成年Col4a1突变、CADASIL或CARASIL小鼠中也未见异常（ $67,73,74,136$$67,73,74,136$67,73,74,13667,73,74,136 ）。

How might these human and mouse BBB studies be reconciled? One possibility is the presence of widespread, but subtle, BBB dysfunction in cSVDs, mainly manifesting as increased permeability to water and ions; permeability to water has not yet been assessed in mouse models. On the other hand, a number of confounding factors that could mimic or mask BBB leakage can affect dynamic contrast-enhanced MRI measurements (137). Moreover, hotspot sites of BBB leakage may reflect the presence of recent microinfarcts (73).
这些人类和小鼠血脑屏障（BBB）研究如何解释？一种可能性是，cSVD中存在广泛但轻微的BBB功能障碍，主要表现为对水和离子的通透性增加；目前尚未在小鼠模型中评估对水的通透性。另一方面，一些可能模仿或掩盖BBB渗漏的混杂因素会影响动态对比增强MRI测量（137）。此外，BBB渗漏的热点区域可能反映近期微梗塞的存在（73）。

DTI along the PVS (DTI-ALPS) around deep medullary veins is an emerging noninvasive technique for evaluating the glymphatic system in humans. The ALPS index represents the CSF efflux function along the perivenous spaces, although additional validation studies are needed (138). Three recent studies performed in pop-ulation-based cohorts or in patients with sporadic cSVD showed that the DTI-ALPS index was negatively related to the presence and severity of cSVD MRI markers (WMH, lacunes, microbleeds, visible PVS in the basal ganglia, and brain atrophy), suggestive of a declined glymphatic function (139-141). Another small case-control study reported a lower DTI-ALPS index in CADASIL patients compared with controls and an association between the DTI-ALPS index and disease (neuroimaging and clinical) severity (142). However, one potential limitation of these studies is that the DTIALPS index is derived from the DTI signal, which is particularly sensitive to WM damages in cSVD and that none of these studies controlled for conventional DTI measures. Studies in mice have shown that aging is associated with progressive glymphatic system dysfunction, manifesting as reductions in both glymphatic influx and efflux. Two factors are primarily responsible for reduced glymphatic influx: decreased arterial wall compliance, which reduces the perivascular pumping of CSF, and depolarization of aquaporin 4, which decreases the transport of fluid across astrocytic endfeet into the brain (143). Glymphatic efflux is likely reduced because of a decrease in the number and diameter of meningeal lymphatics (144). Acute hypertension strongly slows CSF influx in PVSs by increasing backflow (116) and glymphatic transport, both influx and efflux, is altered in spontaneously hypertensive rats (145). A recent study suggested a reduction in glymphatic influx in Notch3KO mice, possibly because of decreased contractility of cerebral arteries or a reduced number of PVMs $(66,146)$$(66,146)$(66,146)(66,146).
沿PV静脉（PVS）的弥散张量成像（DTI-ALPS）是评估人类甘淋巴系统的一种新兴无创技术。ALPS指数反映了脑脊液沿静脉周围间隙的流出功能，尽管仍需进一步验证研究（138）。三项近期研究在人群基线队列或散发性小血管病变（cSVD）患者中发现，DTI-ALPS指数与cSVD磁共振成像（MRI）标志物（白质高信号（WMH）、脑梗死灶（lacunes）、微出血、基底节区可见脑静脉（PVS）及脑萎缩）的发生率和严重程度呈负相关，提示甘淋巴功能减退（139-141）。另一项小型病例对照研究发现，CADASIL患者的DTI-ALPS指数低于对照组，且DTI-ALPS指数与疾病（神经影像学和临床）严重程度相关（142）。然而，这些研究的一个潜在局限性是，DTIALPS指数来源于DTI信号，而DTI信号对cSVD中的WM损伤特别敏感，且这些研究均未控制传统DTI指标。小鼠研究表明，衰老与甘淋巴系统功能障碍进展相关，表现为甘淋巴流入和流出均减少。减少脑脊液淋巴系统流入的两个主要因素是：动脉壁顺应性降低，导致脑脊液的周围血管泵送减少；以及水通道蛋白4的去极化，导致星形胶质细胞足突将液体运入大脑的通透性降低（143）。脑脊液淋巴系统外流可能减少是因为脑膜淋巴管的数量和直径减少（144）。急性高血压通过增加逆流显著减缓PVS中的脑脊液流入（116），且自发性高血压大鼠的脑脊液淋巴系统运输（包括流入和流出）均发生异常（145）。 最近的一项研究表明，Notch3KO小鼠的甘淋巴液流入量减少，这可能与脑动脉收缩力下降或脑微血管（PVMs）数量减少有关。

In summary, emerging evidence suggests that the glymphatic system is compromised in cSVD and that impaired CSF/ISF dynamics may participate in the pathogenesis, but this warrants further studies.
综上所述，现有证据表明，cSVD患者的甘淋巴系统功能受损，且脑脊液/脑组织间液（CSF/ISF）动力学异常可能参与其发病机制，但这一假设仍需进一步研究验证。

Studies in patients and experimental models suggest that functional vascular changes appear years (in humans) or weeks/ months (in mice) after exposure to risk factors, but before the appearance of brain lesions. These changes may include stiffening of large arteries, a reduction in dilation capacity and blood flow, attenuation of NVC, subtle BBB leakage, and glymphatic system dysfunction. Nevertheless, much work is still needed to finely map
研究表明，在患者和实验模型中，功能性血管变化在暴露于危险因素后数年（人类）或数周/数月（小鼠）内出现，但早于脑部病变的出现。这些变化可能包括大动脉僵硬、扩张能力及血流减少、NVC减弱、微小血脑屏障渗漏以及甘淋巴系统功能障碍。然而，仍需进一步研究以精确绘制
the time course of these changes and assess the causal relationships between these changes and disease manifestations. Going forward, studies in patients with monogenic cSVDs may overcome the confounding issue of heterogeneity of patients with sporadic cSVDs, who may simultaneously display comorbidities and other neurodegenerative processes. It is also worth noting that research to date has tended to focus on WM lesions, with small subcortical infarcts and lacunes receiving less notice, despite the fact that lacune count is a strong predictor of disability and cognitive impairment $(147,148)$$(147,148)$(147,148)(147,148).
这些变化的时间进程，并评估这些变化与疾病表现之间的因果关系。未来，针对单基因cSVD患者的研究可能克服散发性cSVD患者异质性带来的混杂问题，因为后者可能同时存在合并症和其他神经退行性病变过程。值得注意的是，迄今为止的研究主要关注白质病变，而较小的皮层下梗死和腔隙则未受到足够关注，尽管腔隙数量是残疾和认知障碍的强预测因素 $(147,148)$$(147,148)$(147,148)(147,148) 。

Although experimental studies have highlighted candidate mechanisms, elucidating the mechanistic chains linking risk factors, vascular changes, and brain lesions remains a daunting challenge. A first issue to clarify is which cell type(s) are involved and at what steps of the pathogenic process. The endothelial cell is the cornerstone in the regulation of CBF and BBB , and endo-thelium-dependent functions, such as NVC, are affected early during aging and hypertension or in the setting of pathogenic variants. On the basis of these observations, it has been proposed that cSVDs are initiated in the endothelium and that endothelial dysfunction is a key driver of vascular pathology (149). However, mural cells are also critical effector cells of major brain vessel functions and are certainly key contributors that must not be overlooked. In particular, human and rodent studies indicate that loss of arterial SMCs is a common denominator in many cSVDs, a linkage underscored by the observation that the most aggressive cSVD forms are associated with more severe loss of arterial SMCs. Several recent studies have also highlighted PVMs and perivascular fibroblasts, another major resident cell of PVS, as additional important candidate cellular mediators. A second question pertains to the molecular pathways that lead to vascular cell loss or dysfunction. Genetic, molecular, proteomic, and functional studies point to an important role for proteins of the microvascular ECM as a convergent mechanism in cSVDs $(8,150)$$(8,150)$(8,150)(8,150). Identifying shared molecular pathways among cSVDs would trigger a quantum leap in the development of therapeutic strategies. Another issue relates to the respective contributions of different microvascular compartments. The observation that the ACT zone is hypermuscularized in ICH-related cSVDs and less muscularized in cSVDs with a mostly ischemic presentation suggests that changes in the properties or density of mural cells in this segment could influence the hemorrhagic versus ischemic presentation of cSVDs (Figure 3). Therefore, in-depth molecular, structural, and functional characterizations of each microvascular compartment in distinct cSVD models could potentially provide insight into the relationship between vessel changes and brain damage.
尽管实验研究已指出潜在机制，但阐明风险因素、血管变化与脑损伤之间机制链条仍面临巨大挑战。首先需明确参与其中的细胞类型及其在病理过程中的具体阶段。内皮细胞是调节脑血流（CBF）和血脑屏障（BBB）的关键细胞，其依赖于内皮细胞的功能（如非血管生成性脑出血，NVC）在衰老、高血压或病理性变异背景下早期即受影响。基于这些观察，有研究提出，cSVDs的发生始于内皮细胞，内皮功能障碍是血管病理学的关键驱动因素（149）。然而，血管壁细胞也是大脑主要血管功能的关键效应细胞，其作用不容忽视。特别是，人类和啮齿类动物研究表明，动脉平滑肌细胞（SMCs）的丢失是许多cSVD的共同特征，这一关联在最严重的cSVD形式与更严重的动脉SMCs丢失相关性中得到进一步证实。近期多项研究还指出，PVMs和周围血管成纤维细胞（PVS中的另一类主要驻留细胞）是额外的关键细胞介质候选者。第二个问题涉及导致血管细胞丢失或功能障碍的分子通路。遗传学、分子生物学、蛋白质组学和功能研究均指出，微血管外基质（ECM）中的蛋白质在cSVD中作为汇聚机制发挥重要作用。识别cSVDs中的共同分子通路将为治疗策略的开发带来革命性进展。另一个问题涉及不同微血管 compartment 的各自贡献。 观察到在与脑出血相关的cSVD中，ACT区呈现肌肉化程度增高，而在以缺血表现为主的cSVD中肌肉化程度较低，这提示该区域壁细胞的性质或密度变化可能影响cSVD的出血性与缺血性表现（图3）。因此，对不同cSVD模型中各微血管室进行深入的分子、结构和功能特征分析，可能为血管变化与脑损伤之间的关系提供新的见解。

As noted above, cSVDs are especially prevalent with aging. cSVDs and neurodegenerative diseases share similar risk factors and often co-occur. Consequently, other neurodegenerative pathologies can contribute to the clinical presentation. Another major challenge will thus be to clarify whether these two pathologies progress independently of each other or exhibit synergistic interactions.
如上所述，cSVDs在衰老过程中尤为常见。cSVDs与神经退行性疾病具有相似的危险因素，且常同时发生。因此，其他神经退行性病理可能对临床表现产生影响。另一个重大挑战将是明确这两种病理是否独立进展，还是存在协同作用。

In conclusion, cSVDs have an enormous impact on human health. Fortunately, the field is now advancing rapidly. Large collaborative research networks that bring together complementary expertise from basic science laboratories to clinics dedicated to
综上所述，cSVDs对人类健康具有深远影响。令人欣慰的是，该领域正迅速发展。目前，大型跨学科研究网络正逐步形成，这些网络汇聚了从基础科学实验室到临床研究机构的专家，致力于
cSVDs should enable further breakthroughs in the near future, bringing us closer to the development of therapeutics that can slow the progression of these devastating diseases.
cSVDs有望在不久的将来实现进一步突破，推动我们向开发能够延缓这些致命疾病进展的治疗方法迈进。

We thank David Hill-Eubank (University of Vermont, Burlington, Vermont, USA) for critical reading and editing of the manuscript. We apologize to all our colleagues whose work has not been mentioned owing to space constraints. The Joutel lab is supported by the National Research Agency, France (grants ANR-16-
我们感谢大卫·希尔-尤班克（美国佛蒙特大学伯灵顿分校）对本文稿的仔细阅读和修改。由于篇幅限制，未能提及所有同事的工作，我们深表歉意。朱特尔实验室得到法国国家研究署（ANR-16-）的资助。

RHUS-0004 and ANR-22-NEU2-0004-01), the US NIH (grant 1RF1NS128963), the Leducq Foundation for Cardiovascular Research (Leducq Transatlantic Network of Excellence 22CVD01 BRENDA), and Fondation pour la Recherche Médicale (PROJET EQU202203014672).
RHUS-0004 和 ANR-22-NEU2-0004-01)，美国国立卫生研究院（NIH，资助编号 1RF1NS128963），莱杜克心脏病研究基金会（莱杜克大西洋卓越网络 22CVD01 BRENDA），以及医学研究基金会（项目编号：EQU202203014672）资助。

Address correspondence to: Anne Joutel, Inserm U1266, Institute of Psychiatry and Neurosciences of Paris, 102-108 rue de la Santé, 75014 Paris, France. Phone: 33.1.40.78.92.96; Email: anne.joutel@ inserm.fr.
请将信件寄至：Anne Joutel，法国国家健康与医学研究院（Inserm）U1266实验室，巴黎精神病学与神经科学研究所，102-108 rue de la Santé，75014巴黎，法国。电话：33.1.40.78.92.96；电子邮件：anne.joutel@inserm.fr。

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