A murine model of cerebral cavernous malformations with acute hemorrhage

Maderna, Claudio; Pisati, Federica; Tripodo, Claudio; Dejana, Elisabetta; Malinverno, Matteo

doi:10.1016/j.isci.2022.103943

Cited by 7 publications

(16 citation statements)

References 47 publications

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“…1B, Supplemental Fig 1). We also observed that among genes associated with coagulation pathways in CCM, Procr (EPCR) 23, 25, 26 is the best candidate gene to differentiate between disease severities (Supplemental Fig 1). These results suggest that while hypoxia and angiogenesis signaling are important in the CCM lesion formation 22 , neuroinflammation signaling may play a more important role in the progression and chronic stages.…”

Section: Resultsmentioning

confidence: 74%

“…while others may have a propensity to become thrombotic (high levels in PAI-1, TSP1, VWF, low in tPA, and inflammation) 23,73 . It is also possible that pro-thrombotic signals in chronic CCM lesions overcome the local anti-coagulant vascular domain 25 and promote immunothrombosis in largely inflamed lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that polymorphisms in inflammatory pathways (e.g., Tlr4 signaling) contribute to variability in CCM disease severity 54–56 and the depletion of B lymphocytes in a genetically sensitized CCM mouse model reduces the maturation and propensity for chronic bleedings 57 . Recent studies in human and mouse models show that inflammation contributes to brain vascular malformations 22, 23, 57–59 . These observations provide direct evidence that inflammation plays a critical role in CCM lesion maturation into the clinical manifestation of CCM disease.…”

Section: Discussionmentioning

confidence: 99%

“…The data establish that the potential mechanistic crosstalk between astrocytes and CCM endothelium can trigger recruitment of inflammatory cells, arising from both brain parenchyma (microglia) and periphery immune system (leukocytes) into mature CCM lesions, that could potentially propagate lesion growth, thrombosis, and bleeding. Accordingly, altered levels of several genes associated with blood coagulation, TSP1 ( Thbs1 ), EPCR ( Procr ), TM ( Thbd ), VWF, tPA ( Plat ), indicate that in the chronic model, some CCM lesions may have a propensity to bleeding (high levels in EPCR and TM and TFPI) while others may have a propensity to become thrombotic (high levels in PAI-1, TSP1, VWF, low in tPA, and inflammation) 23, 73 . It is also possible that pro-thrombotic signals in chronic CCM lesions overcome the local anti-coagulant vascular domain 25 and promote immunothrombosis in largely inflamed lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, histopathological hallmarks identified in human CCM brain tissue are closely recapitulated in the central nervous system (CNS) of genetically sensitized CCM mouse models 17, 18 and, more recently observed, in chronic CCM mouse models using inducible brain endothelial-specific genetic inactivation of CCM genes [19][20][21][22][23] . These CCM animal models have been crucial to unveiling transition phases in CCM lesion genesis that range from early-stage isolated caverns (stage 1) during CCM lesion formation to late-stage multi-cavernous lesions (stage 2) containing hemosiderin deposits and immune cell infiltration (characteristics of human active CCM lesions) (18).…”

Section: Introductionmentioning

confidence: 99%

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Neuroinflammation plays a critical role in cerebral cavernous malformation disease

Lai

Nelsen

Frias-Anaya

et al. 2022

Preprint

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BackgroundCerebral Cavernous Malformations (CCMs) are neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). CCMs affect ∼1/200 children and adults, and no pharmacologic therapy is available. CCM lesion count, size, and aggressiveness vary widely among patients of similar ages with the same mutation or even within members of the same family. However, what determines the transition from quiescent lesions into mature and active (aggressive) CCM lesions is unknown.MethodsWe use genetic, RNA-seq, histology, flow cytometry and imaging techniques to report the interaction between CCM-endothelium, astrocytes, leukocytes, microglia/macrophages, neutrophils (CALMN interaction) during the pathogenesis of CCMs in the brain tissue.ResultsExpression profile of astrocytes in adult mouse brains using translated mRNAs obtained from the purification of EGFP-tagged ribosomes (Aldh1l1-EGFP/Rpl10a) in the presence or absence of CCM lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) identifies a novel gene signature for neuroinflammatory astrogliosis. CCM reactive astrocytes have a neuroinflammatory capacity by expressing genes involved in angiogenesis, chemotaxis, hypoxia signaling, and inflammation. RNA-seq analysis on RNA isolated from brain endothelial cells (BECs) in chronic Pdcd10BECKO mice (CCM-endothelium), identified crucial genes involved in recruiting inflammatory cells and thrombus formation through chemotaxis and coagulation pathways. In addition, CCM- endothelium was associated with increased expression of Nlrp3 and Il1b. Pharmacological inhibition of NLRP3 significantly decreased inflammasome activity as assessed by quantification of a fluorescent indicator of caspase-1 activity (FAM-FLICA caspase-1) in BECs from Pdcd10BECKO in chronic stage. Importantly, our results support the hypothesis of the crosstalk between astrocytes and CCM endothelium that can trigger recruitment of inflammatory cells arising from brain parenchyma (microglia) and the peripheral immune system (leukocytes) into mature active CCM lesions that propagate lesion growth, immunothrombosis, and bleedings. Unexpectedly, partial or total loss of brain endothelial NF-kB activity (using Ikkbfl/fl mice) in chronic Pdcd10BECKO mice does not prevent lesion genesis or neuroinflammation. Instead, this resulted in elevated number of lesions and immunothrombosis, suggesting that therapeutic approaches designed to target inflammation through endothelial NF-kB inhibition may contribute to detrimental side effects.ConclusionsOur study reveals previously unknown links between neuroinflammatory astrocytes and inflamed CCM endothelium as contributors that trigger leukocyte recruitment and precipitate immunothrombosis in CCM lesions. However, therapeutic approaches targeting brain endothelial NF-kB activity may contribute to detrimental side effects.

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Section: Resultsmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuroinflammation plays a critical role in cerebral cavernous malformation disease

Lai

Nelsen

Frias-Anaya

et al. 2022

Preprint

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Histological quantification of cerebral cavernous malformations in the murine brain

2022

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Behavioral impairments are linked to neuroinflammation in mice with Cerebral Cavernous Malformation disease

Offenberger,

Chen,

Rossitto

et al. 2024

Preprint

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BackgroundCerebral Cavernous Malformations (CCMs) are neurovascular abnormalities in the central nervous system (CNS) caused by loss of function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3) genes. One of the most common symptoms in CCM patients is associated with motor disability, weakness, seizures, stress, and anxiety, and the extent of the symptom or symptoms may be due to the location of the lesion within the CNS or whether multiple lesions are present. Previous studies have primarily focused on understanding the pathology of CCM using animal models. However, more research has yet to explore the potential impact of CCM lesions on behavioral deficits in animal models, including effects on short-term and long-term memory, motor coordination, and function.MethodsWe used the accelerating RotaRod test to assess motor and coordination deficits. We also used the open field test to assess locomotor activity and pathology-related behavior and Pavlovian fear conditioning to assess short—and long-term memory deficits. Our behavioral studies were complemented by proteomics, histology, immunofluorescence, and imaging techniques. We found that neuroinflammation is crucial in behavioral deficits in male and female mice with neurovascular CCM lesions (Slco1c1-iCreERT2; Pdcd10fl/fl; Pdcd10BECKO).ResultsFunctional behavior tests in male and femalePdcd10BECKOmice revealed that CCM lesions cause sudden motor coordination deficits associated with the manifestation of profound neuroinflammatory lesions. Our findings indicate that maturation of CCM lesions inPdcd10BECKOmice also experienced a significant change in short- and long-term memory compared to their littermate controls,Pdcd10fl/flmice. Proteomic experiments reveal that as CCM lesions mature, there is an increase in pathways associated with inflammation, coagulation, and angiogenesis, and a decrease in pathways associated with learning and plasticity. Therefore, our study shows thatPdcd10BECKOmice display a wide range of behavioral deficits due to significant lesion formation in their central nervous system and that signaling pathways associated with neuroinflammation and learning impact behavioral outcomes.ConclusionsOur study found that CCM animal models exhibited behavioral impairments such as decreased motor coordination and amnesia. These impairments were associated with the maturation of CCM lesions that displayed a neuroinflammatory pattern.

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A murine model of cerebral cavernous malformations with acute hemorrhage

Cited by 7 publications

References 47 publications

Neuroinflammation plays a critical role in cerebral cavernous malformation disease

Neuroinflammation plays a critical role in cerebral cavernous malformation disease

Histological quantification of cerebral cavernous malformations in the murine brain

Behavioral impairments are linked to neuroinflammation in mice with Cerebral Cavernous Malformation disease

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