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Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.

Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non‐invasive pharmacological therapies. Here, we present the results of several unbiased small‐molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology‐based target prediction tool to integrate the results with the whole‐transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small‐molecule‐based therapies. We found indirubin‐3‐monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss‐of‐CCM phenotypes in human endothelial cells. Our multi‐organism‐based approach reveals new components of the CCM regulatory network and foreshadows novel small‐molecule‐based therapeutic applications for suppressing this devastating disease in patients. Synopsis Currently, the only treatment for cerebral cavernous malformation (CCM) vasculature lesions is surgery. This study by Otten et al establishes a multi‐organismal pharmacological approach to suppress the formation of new lesions or to regress existing ones. Many small molecule compounds alleviating the loss of CCM proteins were identified in suppression screens in C. elegans and zebrafish. DePick, a prediction programme for relevant protein targets of active compounds, was used to identify relevant molecular pathways and CCM‐related drug targets. Indirubin‐3‐monoxime (IR3mo) alleviated the lesion burden in preclinical CCM mouse models. Future experiments with IR3mo will help to unravel the CCM pathobiology. Graphical Abstract Currently, the only treatment for cerebral cavernous malformation (CCM) vasculature lesions is surgery. This study by Otten et al establishes a multi‐organismal pharmacological approach to suppress the formation of new lesions or to regress existing ones.

INTRODUCTION Genetics of cerebral amyloid angiopathy (CAA) remains understudied. METHODS We assessed variants in Alzheimer's disease (AD) risk factor genes and differential diagnosis genes by performing exome sequencing among 78 patients with early‐onset definite or probable CAA, after negative screening for APP mutation or duplication. RESULTS Among 14 genes involved in non‐Aβ CAA, or vascular leukoencephalopathies, we detected pathogenic NOTCH3 variants in two patients, who exhibited lobar hematomas at the ages of 58 and 65, leading to a diagnosis redirection toward CADASIL. Of the remaining 76 patients, 23.1% carried at least one apolipoprotein E (APOE) ε2 allele and 43.6% carried at least one APOE ε4 allele, known as CAA risk factors. A total of 15 out of 76 (19.7%) carried either a loss‐of‐function or a rare predicted damaging missense or known AD risk variant in SORL1, TREM2, ABCA7, ABCA1, and ATP8B4. DISCUSSION Exome sequencing allowed the redirection toward CADASIL in two patients and suggested shared genetic factors between AD and CAA, beyond the APOE gene. Highlights The genetic component of cerebral amyloid angiopathy (CAA) remains understudied. Rare differential diagnoses such as CADASIL should be considered, even in cases of cerebral hemorrhage. Our study suggests shared genetic factors between AD and CAA, beyond the APOE gene. Rare variants in SORL1, TREM2, ABCA7, ABCA1 and ATP8B4 might be susceptibility factors in early‐onset CAA.,

Abstract BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.

Cerebral cavernous malformations associated with loss of function of Ccm1 are shown to be formed by endothelial cells undergoing endothelial-to-mesenchymal transition (EndMT) induced by TGF-β and BMP signalling; inhibition of TGF-β and BMP signalling prevents EndMT and the appearance of CCM lesions. CCM disease pathology Cerebral cavernous malformation (CCM) is a genetic disease causing lesions of the brain vasculature that can lead to seizures and stroke. Neurosurgery is the only treatment offered today. CCM lesions are caused by loss-of-function mutations in one of three genes: CCM1 , CCM2 and CCM3 . Elisabetta Dejana and colleagues show that lesions associated with loss of function of CCM1 are formed by endothelial cells undergoing endothelial-to-mesenchymal transition (EndMT), induced by activation of transforming growth factor-β (TGF-β) signalling. They show that inhibition of TGF-β signalling prevents EndMT and the appearance of CCM lesions in vivo . Inhibitors of various steps of the TGF-β and bone morphogenetic protein signalling pathways might therefore be candidates to reduce or reverse the development of CCM lesions. Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1 ), CCM2 ( OSM ) and CCM3 ( PDCD10 ), and occurs in both sporadic and familial forms 1 . Recent studies 2 , 3 , 4 , 5 , 6 , 7 have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear 8 . Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions 9 . Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium 10 , 11 , 12 . Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.

Circulation of blood throughout the cardiovascular system results in biomechanical forces that profoundly influence vessel development and maintenance. Fluid shear stress along the inner lining of blood vessels imparts mechanical forces upon vascular cells. Endothelial cells (ECs), which line all blood and lymphatic vessels, are exquisitely equipped to sense mechanical forces and to transduce these stimuli into biochemical signals, which control their proliferation, migration, cytoskeleton organization, and cell-cell adhesion. Vascular malformations can arise when patterns of blood flow change or when vascular cells develop a disturbed response to hemodynamic forces due to genetic mutations. The influence of biomechanical cues on genetically vulnerable cells provides a promising therapeutic avenue. Vascular malformations are often incurable, and patients experience lifelong chronic pain, disfigurement, or even premature death. A major obstacle to developing useful therapies is the poor understanding of the molecular underpinnings of these vascular defects. Tangible therapeutic approaches may be based on the novel idea that vascular cell responses to blood flow can be normalized using pharmacological modulation.

Rare genetic variants are expected to play an important role in disease and several statistical methods have been developed to test for disease association with rare variants, including variance-component tests. These tests however deal only with binary or continuous phenotypes and it is not possible to take advantage of a suspected heterogeneity between subgroups of patients. To address this issue, we extended the popular rare-variant association test SKAT to compare more than two groups of individuals. Simulations under different scenarios were performed that showed gain in power in presence of genetic heterogeneity and minor lack of power in absence of heterogeneity. An application on whole-exome sequencing data from patients with early- or late-onset moyamoya disease also illustrated the advantage of our SKAT extension. Genetic simulations and SKAT extension are implemented in the R package Ravages available on GitHub (https://github.com/genostats/Ravages).

Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. Exome sequencing from 39 trios were analyzed. We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of patients with a genetic form of the disease are now available. In addition, three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.