Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease
2016; Lippincott Williams & Wilkins; Volume: 47; Issue: 2 Linguagem: Inglês
10.1161/strokeaha.115.009627
ISSN1524-4628
AutoresMasafumi Ihara, Yumi Yamamoto,
Tópico(s)Intracerebral and Subarachnoid Hemorrhage Research
ResumoHomeStrokeVol. 47, No. 2Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBEmerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease Masafumi Ihara, MD, PhD and Yumi Yamamoto, PhD Masafumi IharaMasafumi Ihara From the Departments of Stroke and Cerebrovascular Diseases (M.I.) and Regenerative Medicine and Tissue Engineering (M.I., Y.Y.), National Cerebral and Cardiovascular Center, Suita, Japan. and Yumi YamamotoYumi Yamamoto From the Departments of Stroke and Cerebrovascular Diseases (M.I.) and Regenerative Medicine and Tissue Engineering (M.I., Y.Y.), National Cerebral and Cardiovascular Center, Suita, Japan. Originally published7 Jan 2016https://doi.org/10.1161/STROKEAHA.115.009627Stroke. 2016;47:554–560Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 Cerebral small vessel disease (SVD), which affects small arteries, arterioles, venules, and capillaries in the brain, has long been associated with cognitive impairment and dementia. Pathologically, characteristic features include (1) vasculopathy of the small cerebral vessels,1 (2) lacunar infarcts,2 (3) microbleeds (lobar or deep),3 (4) widened perivascular spaces (Virchow–Robin spaces),4,5 (5) focal or diffuse white matter (WM) changes (often seen as hyperintensities on magnetic resonance imaging),6 and (6) microinfarcts.7,8 SVD is a spectrum of abnormalities, with the majority of patients experiencing symptoms from both ischemic and hemorrhagic changes in varying degrees as the disease progresses.9 WM damage is commonly found in SVD, and enlarged perivascular spaces, lacunar infarction, and deep microbleeds coexist with lipohyalinosis,10 whereas cortical microinfarcts and lobar microbleeds are more frequently found in cerebral amyloid angiopathy.11 Such pathological changes also frequently accompany the hallmarks of Alzheimer's disease and previously were only evident by postmortem histopathological examinations12 but now often visible with modern neuroimaging.13 Despite improvements in clinical/radiological markers available for the characterization of SVD, none are specific for SVD and there remain other factors yet to be identified. Here, we aim to review 4 emerging factors involved in the pathogenesis of SVD, with particular emphasis on the endothelial dysfunction that leads to blood–brain barrier (BBB) disruption, as well as discuss potential future therapeutic strategies. The 4 factors covered in our topical review are (1) hypertension and salt intake, (2) infection and inflammation, (3) large and small artery cross talk, and (4) cell–cell interaction in the BBB. For a comprehensive view of SVD pathogenesis, readers may refer to the already published reviews.1,10,14Pathological Cascade of SVD: Roles of Hypertension and SaltThe most common risk factor of SVD is hypertension, but multiple factors frequently coexist,15 as is the case in the dynamic polygon hypothesis of vascular cognitive impairment (VCI).16 The classical so-called lacunar hypothesis attributed lacunar lesions to the occlusion of small perforating cerebral arteries (details of which are discussed elsewhere17,18). In the classical pathway, vascular risk factors (VRFs), such as hypertension, induce vasculopathy, followed by thrombotic occlusion and eventually lacunar stroke (Figure 1, left pathway). However, vessel occlusion is rare in patients with lacunar stroke, whereas vasculopathy and disintegration of the arteriolar wall are common.2 SVD is often treated with antiplatelet therapy, such as aspirin or clopidogrel, with the aim of preventing vessel occlusion, and single antiplatelet therapy successfully reduces the risk of recurrent stroke by ~30%.19Download figureDownload PowerPointFigure 1. Classical and alternative pathological cascade of small vessel disease (SVD). Emerging factors, such as salt intake, chronic inflammation, and gut infection, may have a role in SVD pathogenesis. Large vessel disease (LAD) may induce blood–brain barrier (BBB) dysfunction through large and small artery cross talk (see text for details). Failure in communication networks between BBB cell components may also lead to BBB dysfunction. CMBs indicates cerebral microbleeds; PVS, enlarged perivascular space; and WMH, white matter hyperintensities.Yet SVD seems not entirely a blood pressure–dependent process, despite the existence of obvious hypertension-related changes in arterial structure. Several studies have suggested an alternative cascade of events may also underlie SVD pathogenesis (Figure 1, right), though the classical pathway associated with VRFs still account for important aspects of SVD. In the alternative pathway, endothelium seems to play a key role.15 Two rodent models with systemic hypertension, spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHR-SPs), both exhibit endothelial dysfunction, such as reduced phosphorylated endothelial nitric oxide synthase expression20 and disrupted BBB, respectively.21 SHRs and SHR-SPs also show similar degrees of hypertension but different levels of WM damage.22 SHR-SPs manifest damage in the endothelium, matrix protein, glial cells, and myelin long before hypertension develops, indicating a predisposition to SVD, with further damage when hypertension does develop.23,24 The data suggest that factors other than hypertension also contribute to the onset of WM damage, that is, gene–environment interactions. Differential gene effects can be observed in humans with WM hyperintensities (WMH).25 An magnetic resonance imaging study in patients with SVD showed not only that hypertension could be a predictor of WMH damage in patients with mild stroke but also that salt intake itself is associated with WMH, independent of hypertension.15 It is well known that there are salt-resistant and salt-sensitive hypertensive patients, the latter of whom has been associated with greater endothelial dysfunction, characterized by defective endothelium-dependent vasodilation.26 Several other studies on dietary salt in humans have not only revealed its indirect (hypertension-mediated), but also its direct, effect on endothelium. Healthy subjects who received a high-salt meal showed impaired endothelium-dependent vasodilation without any blood pressure changes, possibly because of reduced endothelial nitric oxide synthase activity from increased plasma sodium concentrations.27 Salt intake has also been associated with inflammatory response; brain and serum levels of an inflammatory marker expressed by endothelial cells, E-selectin, are significantly increased in SHR-SPs after salt intake but unchanged in SHRs.28 Hence, as demonstrated in the effects of salt and hypertension on endothelial dysfunction, VRFs may directly and indirectly cause endothelial dysfunction, and subsequent BBB breakdown can lead to enlarged perivascular spaces, cerebral microbleeds, and WM changes.29The 2 pathways described above do not occur in isolation but rather interact to exacerbate small vessel pathology, although the alternative pathway may contribute to a greater extent in the development of SVD. The fact that VRFs explain only ~2% of WMH variance13 suggests that unconfirmed factors may contribute to small vessel pathology, such as WM disease.Inflammation, Infection, and Brain–Gut Axis in SVDThe search for risk loci of ischemic stroke with genome-wide association studies has borne little fruit,30 partly because genome-wide association study has not considered multiple factors in aggregate, for example, epistasis.31 Discrepancy exists between high heritability estimates (>50%) for WMH obtained in twin and family history studies32 and relatively low estimates (~25%) derived from genome-wide association studies.33 A factor influencing such missing heritability is gene–environment interactions; thus, measuring environment rigorously and analyzing it against genome-wide association studies data could be a useful strategy. In fact, interaction between VRFs and gene expression could help explain part of the missing heritability, as WMH volume attributable to common genetic variants has been estimated to be 45% for hypertensives against 13% for nonhypertensives.33 Another environmental factor, inflammation (namely, chronic inflammation) is also related to SVD pathology (Figure 1), including lacunar stroke, enlarged perivascular space, and subsequent WMH.34,35 Consequently, many studies have focused on the relationship between inflammation and SVD. It has been demonstrated that inflammation primarily targets endothelial cells and results in BBB breakdown,36,37 probably because of neopterin and cytokines secreted by activated monocytes/macrophages,34 subsequently disrupting the extracellular matrix.38 The question is what triggers inflammation in the first place? We mentioned salt-induced inflammation in the previous section, but there are several other potential sources in older people, including joint inflammation, C-reactive peptides from the liver (after the ingestion of a carbohydrate-rich meal), serum amyloid P, rheumatoid arthritis, and stroke itself. Inflammation associated with infection has also been considered important both before and after stroke as a plethora of acute and chronic infectious pathogens may affect susceptibility and prognosis of stroke patients.39 Among the bacteria and viruses that increase the risk of stroke are those affecting the respiratory system, including Chlamydia pneumoniae and influenza but interestingly some are gastrointestinal.The emerging concept of the brain–gut axis,40,41 which proposes that bidirectional signaling between the gastrointestinal tract, or gut microbiota, and the brain is vital for maintaining homeostasis, has gained traction in recent years. For instance, lack of gut microbiota results in reduced anxiety behavior, which can be normalized if microbiota are reconstituted early in life, suggesting gastrointestinal environment has a greater impact on brain development than expected.42 Several other studies have reported an association between the brain–gut axis and various disorders including cardiovascular disease43 and neurodegenerative disorders.40 These studies, however, have focused mainly on the flora in the stomach and lower intestine without taking a major part of the gut, the oral cavity, into consideration.More than 500 bacterial species have been estimated to exist in the oral cavity, and many remain to be identified and characterized.44 Of all the known pathogenic oral bacteria, a few have been linked to cerebrovascular diseases.45,46 Nakano et al46 recently demonstrated that certain strains of Streptococcus mutans are potential risk factors for intracerebral hemorrhage in SHR-SPs and mice with photochemically induced middle cerebral artery occlusion. This corresponds with findings showing periodontal infections to be risk factors for stroke,47,48 and that S. mutans is detected in 100% of samples of atherosclerotic plaques.49S. mutans is a major pathogen in dental caries that can cause bacteremia by dental procedures, such as tooth extraction and periodontal surgery, or even tooth brushing in daily life.50 The hemorrhage-causing S. mutans strains express collagen-binding proteins on their cell surface, enabling them to attach effectively to exposed collagen fibers on the surface of damaged blood vessels and prevent platelet activation, thereby, leading to hemorrhages (Figure 2).46 Consistent with these data, a recent population-based study showed a strong correlation between cerebral microbleeds and collagen-binding proteins–positive S. mutans with a significantly high odds ratio for cerebral microbleeds at 14.4.51 Another dental bacterium, Porphyromonas gingivalis, is also found in atherosclerotic plaques and has been linked to the increased risk of ischemic stroke.52 It was reported that P. gingivalis adheres to and infects endothelial cells not only to increase the expression of endothelial adhesion molecules and promote monocyte/macrophage infiltration but also to produce cysteine proteinase gingipains, which activate protease-activated receptors-1 and -4 on platelets to induce platelet aggregation.53,54 Thus, infection from P. gingivalis could cause SVD pathology through both the classical pathway involving thrombotic occlusion and the alternative pathway, leading to BBB disruption through inflammation.Download figureDownload PowerPointFigure 2. Brain–oral axis. Streptococcus mutans (S. mutans) and Porphyromonas gingivalis (P. gingivalis) are both found in atherosclerotic plaques and suggested to induce hemorrhagic and ischemic stroke, respectively. EC indicates endothelial cell; and RBC, red blood cell.Taken together, oral microbiota seems to affect the brain not only by causing inflammation but also by altering platelet aggregation. Because such oral bacteria do not reside in the stomach or intestine, this mechanism may be called the brain–oral (dental) axis rather than the brain–gut axis, emphasizing the importance of oral interaction. The proximity between the oral cavity and brain may very well contribute to the pathogenesis of cerebral disorders because of the ease in transmission of oral microbiota via blood circulation to the basal location of the brain.Large and Small Artery Cross Talk: Role of Altered Hemodynamics in SVDCerebrovascular changes and related stroke are often categorized under large- and small vessel domains and discussed as if different types of pathologies. Nevertheless, they are a part of continuous circulatory system and their pathology inevitably affects each other. The reduction in the Windkessel effect or hardening of the aorta and common carotid arteries results in elevated systolic blood pressure that damages small vessels and predicts myocardial infarction and stroke.55 Cardiovascular risk factors start to affect the arterial system from very early in life, damaging both large and small arteries through large and small artery cross talk56,57; thus, an excessive transmission of pulse pressure to small cerebral arteries, in response to an increased arterial stiffness, could ultimately impair the cerebral hemodynamics and then reduce cognitive reserve. However, the increased pulsatility index in internal carotid artery and middle cerebral artery in patients with WMH58,59 suggests that stiffened small vessels can induce large artery remodeling and precede large vessel stiffness. It remains controversial whether primary large artery pathology alters small arteries, or vice versa. Thus, SHR-SPs are being used both as a model of lacunar infarct pathology and small vessel arteriopathy60,61 and a model of large artery stroke and middle cerebral artery occlusion, whereas its relevance to SVD had been largely overlooked.62 Large and small artery cross talk has also been demonstrated mainly in rodent chronic cerebral hypoperfusion models, where carotid artery manipulation results in some of the characteristics of SVD, namely, endothelial damage, BBB disruption, and WM damage. Moreover, it has been demonstrated that when chronic cerebral hypoperfusion is further applied to SHRs, WM damage is more extensive than in Wistar Kyoto rats.63Of all the recent rodent models of VCI, the bilateral common carotid artery stenosis mouse model, which uses newly designed microcoils to narrow the bilateral common carotid arteries, has so far been the most reproducible model of chronic hypoperfusion and cognitive impairment over a predictable time course with a very high survival rate (~95%).64 Although the bilateral common carotid artery stenosis model cannot replicate small vessel vasculopathy or lacunar infarcts or model SVD, it possesses advantages in terms of reproducibility of WM pathology, characterized by BBB disruption, glial activation, oxidative stress, and oligodendrocyte loss.65–69 Although clinically there is no direct evidence of an association between carotid stenosis and SVD or cognitive decline, once confounding risk factors are corrected for,13,70,71 altered hemodynamics following bilateral common carotid artery stenosis results in opening of the endothelial tight junction only 2 hours after manipulation, which can be suppressed by matrix metalloproteinase 2 (MMP2) inhibitors.66,68 MMP2, an extracellular matrix degradation enzyme, is also known to degrade the tight junction proteins ZO-1, claudin-5, and occludin, as well as induce BBB breakdown.72 Indeed, MMP2 is upregulated in SHR-SPs and has been associated with WMH in human.61,73 These data suggest that hypoperfusive insult caused by the stenosis of larger arteries may trigger endothelial damage at the capillary level via MMP2. BBB dysfunction results in the leakage of proteins (eg, proteases and immunoglobulins) and fluid through the compromised barrier of the penetrating arteries and eventually leads to the major pathologic features associated with WM lesions, such as demyelination and gliosis.74,75A magnetic resonance imaging pathological correlation study of VCI cases has suggested that the WM damage comprises heterogeneous combinations of widened perivascular spaces, myelin loss, axonal loss, scattered small infarcts, and astrogliosis.76,77 Models that replicate the characteristics of subcortical VCI pathology, as well as the gradual reduction of cerebral blood flow, may greatly advance research in SVD. For instance, another hypoperfusion model in mice (asymmetric common carotid artery surgery model) has offered promise in reproducing WM infarct damage following gradual but not acute cerebral blood flow reduction over 1 month.78 Still, limitations exist in the asymmetric common carotid artery surgery model, including relatively low survival rate (~80%) and limited area of mouse WM available for the pathological evaluation of infarct damage. The lack of rodent models that consistently replicate WM infarct damage may partly explain why many neuroprotective drugs for ischemic stroke or VCI have failed to translate to clinical efficacy, despite earlier success in preclinical experiments using gray matter ischemia models. Improvements in rodent models would greatly help us not only understand the pathogenesis of large/small vessel cross talk and BBB disruption but also aid in the early-phase evaluation of potential SVD treatment strategies.Important Roles of Cell Components of BBB in SVDMany still regard leaking of the BBB as a hypothesis or epiphenomenon. Pathological studies have often downgraded the importance of perivascular spaces as a fixation artifact and have overlooked the shifts in interstitial fluid secondary to BBB leakage, which are visible on imaging. The magnetic resonance imaging mean diffusivity discriminates WMH from normal-appearing WM even within the mild range of WMH severity, suggesting that BBB leak is an early predictor of WM damage.79,80 There are accumulating lines of evidence in support of a pivotal role of the BBB leakage in SVD stroke81–83 and in VCI.84 Therefore, endothelial damage and subsequent BBB breakdown seem to be pivotal factors contributing to the pathogenesis of SVD. Other cellular components of the BBB, including pericytes, astrocytes, and even oligodendrocyte precursor cells, have been suggested to be essential for the maintenance of BBB, though their exact role has yet to be determined.Pericytes and astrocytes are well-known regulators of BBB maturation and maintenance. The role of pericytes in the maintenance of BBB integrity is of particular interest as a recent report has demonstrated that BBB breakdown, indicated by leaking of a contrast agent in the brain and increased platelet-derived growth factor receptor-β in cerebrospinal fluid, is an early event in the aging human hippocampus that might lead to cognitive impairment.85 The importance of pericytes in SVD has been emphasized in studies on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, where the responsible gene NOTCH3 has been shown to be specifically expressed in pericytes, suggesting abnormal interactions between pericytes and endothelial cells contribute to pathogenesis.86 Several studies have reported that the number of platelet-derived growth factor receptor-β–positive pericytes is increased in the WM of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients.87,88 Because pericytes have been suggested to control key neurovascular functions and their loss precedes neurodegenerative changes,89 the increase in platelet-derived growth factor receptor-β–positive pericytes in SVD may account for compensatory processes under chronic hypoperfusion.Although the communication network between pericytes and endothelial cells has been considered in a number of publications, less is known about cell-to-cell communication involving astrocytes. Recent evidence suggests that brain-derived neurotrophic factor secreted by astrocytes promotes oligodendrocyte precursor cell maturation during the recovery from WM ischemic injury.90 Previous reports have also demonstrated that astrocyte–pericyte cross talk regulates tissue survival in central nervous system,91 and that astrocyte–endothelial interactions influence the BBB under both physiological and pathological conditions.92 SHR-SPs also provide evidence of altered glial–endothelial interactions and BBB leak. Genes differently expressed in brains of SHR-SPs of 5, 16, and 21 weeks of age, compared with controls, include those related to glial activity (increased), endothelial tight junctions (reduced), and vascular reactivity (impaired),23 some of which have also been identified in human gene analysis of WMH.25 It has been increasingly recognized that oligodendrocyte precursor cells themselves also play a pivotal role in promoting BBB integrity by the secretion of transforming growth factor-β1.93 Moreover, electron microscopy has demonstrated that oligodendrocyte precursor cells and pericytes directly adhere to and communicate with each other via basal lamina to promote their proliferation and differentiation.94The above data implicate the impact of disrupted cross talk among BBB cell components in the development of disease pathology. Our understanding of the mechanisms of how these interactions are disturbed in pathological conditions is still limited, but it is hoped that future progress in this field could lead to the development of new protective and restorative therapies.Future Perspectives in the Treatment of SVDAs discussed in this review, recent research has indicated that contributors to SVD pathogenesis other than the classic VRFs may all lead to BBB disruption following salt toxicity, inflammation/infection, altered hemodynamics, and damage in BBB cell components. A promising strategy for SVD may, therefore, involve targeting such contributory factors by the restoration of BBB integrity. For instance, considering its direct and indirect (via hypertension) effects on endothelial cells,15 salt restriction may help. Likewise, the normalization of brain–gut (oral/dental) interaction with probiotics, antibiotics, and oral care could exert similar effects. One of the hypertensives, angiotensin II type 1 receptor blockers, may hold promise in halting WM damage because of their suppression of MMP2 upregulation, which can be induced by altered hemodynamics.68 Similarly, synthetic MMP inhibitors would be useful in the restoration of BBB integrity by suppressing extracellular matrix degradation and blocking acute and chronic inflammatory response in vascular endothelial cells.95 The brain renin–angiotensin II system and hypertension in SHR are reported to be attenuated by exercise,96 which preserves small vessel function and is associated with fewer WMH.97 Angiotensin receptor blockers and exercise are also expected to improve large artery remodeling.98 Thus, the recent advancement in the understanding of SVD risk factors and related molecular pathways from animal and human studies may provide clues in the search for potential remedies for SVD (Figure 3). Such treatments may, therefore, focus on rescuing BBB disruption through multiple but interrelated pathways.Download figureDownload PowerPointFigure 3. Targeting multiple pathways leading to blood–brain barrier disruption in small vessel disease (SVD). Because SVD is caused by variable factors converging on blood–brain barrier (BBB) disruption, a promising strategy for SVD would involve targeting such contributory factors for restoration of BBB integrity. Pointed arrows indicate positive regulation, whereas blunt-ended arrows indicate negative regulation (treatment). See text for details. ARB indicates angiotensin II type 1 blocker; LAD, large artery disease; MMP, matrix metalloproteinase; and RAS, renin–angiotensin II system.AcknowledgmentsThe authors would like to thank Dr Ahmad Khundakar (Newcastle University, UK) for his editorial assistance and insightful discussion.Sources of FundingThis work was supported by grants from the Ministry of Health, Labour and Welfare (No. 0605-1 to M.I.); Ministry of Education, Culture, Sports, Science and Technology [Grant-in-Aid for Scientific Research (B), No. 15H04271 to M.I.]; the Takeda Science Foundation (M.I.); and the Takeda Medical Research Foundation (M.I.).DisclosuresNone.FootnotesCorrespondence to Masafumi Ihara, MD, PhD, FACP, Division of Neurology, Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565–8565, Japan. E-mail [email protected]References1. 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