The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Lisowska, Justyna; Rödel, Claudia Jasmin; Manet, Sandra; Miroshnikova, Yekaterina A.; Boyault, Cyril; Planus, Emmanuelle; Mets, Richard De; Lee, Hsiao-Hui; Destaing, Olivier; Mertani, Hichem C.; Boulday, Gwénola; Tournier‐Lasserve, Elisabeth; Balland, Martial; Abdelilah‐Seyfried, Salim; Albiges-Rizo, Corinne; Faurobert, Eva

doi:10.1242/jcs.216093

Cited by 45 publications

(28 citation statements)

References 65 publications

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“…Considering this evidence, our finding that Notch4 is reduced in KRIT1-deficient ECs suggests a potential alternative contribution to the observed upregulation of VCAM-1. Moreover, the augmented expression of VCAM-1 might be also a consequence of the known KRIT1 loss-dependent activation of RhoA/ROCK pathway [13], according to existing evidence [71,72]. However, additional regulatory mechanisms could be also involved, including redox signaling.…”

Section: Resultsmentioning

confidence: 99%

KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction

Sega

Mastrocola

Aquila

et al. 2019

IJMS

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Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence demonstrates that KRIT1 is implicated in the modulation of major redox-sensitive signaling pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, suggesting that its loss-of-function mutations may have pathological effects not limited to CCM disease. The aim of this study was to address whether KRIT1 loss-of-function predisposes to the development of pathological conditions associated with enhanced endothelial cell susceptibility to oxidative stress and inflammation, such as arterial endothelial dysfunction (ED) and atherosclerosis. Silencing of KRIT1 in human aortic endothelial cells (HAECs), coronary artery endothelial cells (HCAECs), and umbilical vein endothelial cells (HUVECs) resulted in increased expression of endothelial proinflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and in enhanced susceptibility to tumor necrosis factor alpha (TNF-α)-induced apoptosis. These effects were associated with a downregulation of Notch1 activation that could be rescued by antioxidant treatment, suggesting that they are consequent to altered intracellular redox homeostasis induced by KRIT1 loss-of-function. Furthermore, analysis of the aorta of heterozygous KRIT1+/− mice fed a high-fructose diet to induce systemic oxidative stress and inflammation demonstrated a 1.6-fold increased expression of VCAM-1 and an approximately 2-fold enhanced fat accumulation (7.5% vs 3.6%) in atherosclerosis-prone regions, including the aortic arch and aortic root, as compared to corresponding wild-type littermates. In conclusion, we found that KRIT1 deficiency promotes ED, suggesting that, besides CCM, KRIT1 may be implicated in genetic susceptibility to the development of atherosclerotic lesions.

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Section: Resultsmentioning

confidence: 99%

KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction

Sega

Mastrocola

Aquila

et al. 2019

IJMS

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Section: Rhoa-rock Signallingmentioning

confidence: 99%

“…KRIT1, CCM2 and CCM3 deficient endothelial cells and human CCM lesion samples display activated RhoA and increased activity of downstream effectors ROCK1 and ROCK2, which consequently phosphorylate myosin light chain (MLC) and MLC phosphatase, leading to inhibition of the latter [62,73,[107][108][109]. This increased RhoA-ROCK signalling results in actomyosin contractility and stress fibre accumulation, impairing migration, invasion and 3D tube formation, and destabilizes endothelial adherens junctions, thereby reducing endothelial barrier function and increasing vascular permeability [62,65,73,108,110,111]. Notably, pharmacologic inhibition of ROCK reverses the increased MLC phosphorylation, actin stress fibres and monolayer permeability seen in KRIT1, CCM2 or CCM3 deficient endothelial cells [62,73,108,110], and also rescued the impaired pulmonary and cerebral vascular leak in KRIT1 +/− and CCM2 +/− heterozygous mice [62,73].…”

Section: Rhoa-rock Signallingmentioning

confidence: 99%

“…This increased RhoA-ROCK signalling results in actomyosin contractility and stress fibre accumulation, impairing migration, invasion and 3D tube formation, and destabilizes endothelial adherens junctions, thereby reducing endothelial barrier function and increasing vascular permeability [62,65,73,108,110,111]. Notably, pharmacologic inhibition of ROCK reverses the increased MLC phosphorylation, actin stress fibres and monolayer permeability seen in KRIT1, CCM2 or CCM3 deficient endothelial cells [62,73,108,110], and also rescued the impaired pulmonary and cerebral vascular leak in KRIT1 +/− and CCM2 +/− heterozygous mice [62,73]. Similarly, the ROCK inhibitors, fasudil and atorvastatin, have recently been shown to reduce lesion burden in CCM3 deficient mice [112].…”

Section: Rhoa-rock Signallingmentioning

confidence: 99%

“…10: 200263 KRIT1 co-immunoprecipitates with both ROCK isoforms, ROCK1 and ROCK2, but apparently impacts their functions differently [8,10]. KRIT1 recruits ROCK2 to VE-cadherin junctions but inhibits ROCK1 kinase activity to ensure proper adhesion to the extracellular matrix and stabilize cell-cell junctions [108]. The molecular basis for these isoform-specific effects is currently unclear, but while ROCK2 knockdown phenocopies the heart defects of kri-1 null zebrafish and the abnormal F-actin and focal adhesion morphologies of KRIT1 and CCM2 null endothelial cells, ROCK1 knockdown restores cortical actin organization and rescues cardiac cushions and ventricular chamber formation in kri-1 mutant zebrafish [108].…”

Section: Rhoa-rock Signallingmentioning

confidence: 99%

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Signalling through cerebral cavernous malformation protein networks

Calderwood

2020

Open Biol.

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Cerebral cavernous malformations (CCMs) are neurovascular abnormalities characterized by thin, leaky blood vessels resulting in lesions that predispose to haemorrhages, stroke, epilepsy and focal neurological deficits. CCMs arise due to loss-of-function mutations in genes encoding one of three CCM complex proteins, KRIT1, CCM2 or CCM3. These widely expressed, multi-functional adaptor proteins can assemble into a CCM protein complex and (either alone or in complex) modulate signalling pathways that influence cell adhesion, cell contractility, cytoskeletal reorganization and gene expression. Recent advances, including analysis of the structures and interactions of CCM proteins, have allowed substantial progress towards understanding the molecular bases for CCM protein function and how their disruption leads to disease. Here, we review current knowledge of CCM protein signalling with a focus on three pathways which have generated the most interest—the RhoA–ROCK, MEKK3–MEK5–ERK5–KLF2/4 and cell junctional signalling pathways—but also consider ICAP1-β1 integrin and cdc42 signalling. We discuss emerging links between these pathways and the processes that drive disease pathology and highlight important open questions—key among them is the role of subcellular localization in the control of CCM protein activity.

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Cerebral vascular malformations: pathogenesis and therapy

He,

Huo,

Sun

et al. 2024

MedComm

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Cerebral vascular malformations (CVMs), particularly cerebral cavernous malformations and cerebral arteriovenous malformations, pose significant neurological challenges due to their complex etiologies and clinical implications. Traditionally viewed as congenital conditions with structural abnormalities, CVMs have been treated primarily through resection, embolization, and stereotactic radiosurgery. While these approaches offer some efficacy, they often pose risks to neurological integrity due to their invasive nature. Advances in next‐generation sequencing, particularly high‐depth whole‐exome sequencing and bioinformatics, have facilitated the identification of gene variants from neurosurgically resected CVMs samples. These advancements have deepened our understanding of CVM pathogenesis. Somatic mutations in key mechanistic pathways have been identified as causative factors, leading to a paradigm shift in CVM treatment. Additionally, recent progress in noninvasive and minimally invasive techniques, including gene imaging genomics, liquid biopsy, or endovascular biopsies (endovascular sampling of blood vessel lumens), has enabled the identification of gene variants associated with CVMs. These methods, in conjunction with clinical data, offer potential for early detection, dynamic monitoring, and targeted therapies that could be used as monotherapy or adjuncts to surgery. This review highlights advancements in CVM pathogenesis and precision therapies, outlining the future potential of precision medicine in CVM management.

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The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Cited by 45 publications

References 65 publications

KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction

KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction

Signalling through cerebral cavernous malformation protein networks

Cerebral vascular malformations: pathogenesis and therapy

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