KRIT1 Protein Depletion Modifies Endothelial Cell Behavior via Increased Vascular Endothelial Growth Factor (VEGF) Signaling

DiStefano, Peter V.; Kuebel, Julia M.; Sarelius, Ingrid H.; Glading, Angela

doi:10.1074/jbc.m114.582304

Cited by 59 publications

(68 citation statements)

References 70 publications

(87 reference statements)

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“…The increase in VEGF expression leads to autocrine binding of VEGFR2 and subsequent activation of downstream angiogenic signaling pathways, suggesting that VEGF expression contributes to a feed-forward pathway promoting the CCM pathologic phenotype. Intriguingly, this study also pointed out that PDCD10, but not CCM2, also increases β-catenin transcriptional activity and VEGF expression (DiStefano et al, 2014). However, PDCD10 deficient cells reportedly exhibit a loss of VEGFR2 signaling and are unable to respond to VEGF stimulation (He et al, 2010).…”

Section: Role Of Angiogenesis In Ccm Pathogenesismentioning

confidence: 68%

“…In addition, there is evidence that CCM proteins ensure the quiescence of endothelial cells and inhibit angiogenic responses by either activating the Delta-Notch signaling axis (Schulz et al, 2015, Wustehube et al, 2010, You et al, 2013), inhibiting vascular endothelial growth factor (VEGF) and MAPK/ERK signaling (Cullere et al, 2015, DiStefano et al, 2014, Zhu et al, 2010), or preventing the β1 integrin-dependent activation of a mechanotransduction pathway mediated by the blood flow-sensitive transcription factor Kruppel-like factor 2 (KLF2) (Renz et al, 2015). …”

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

“…Increased permeability can contribute to the activation of junctionally-regulated transcriptional factors, such as β-catenin (Glading and Ginsberg, 2010) and Kaiso (unpublished data), both seen in the absence of CCM proteins. These can then upregulate both pro-inflammatory and pro-angiogenic signals, such as VEGF expression (DiStefano et al, 2014), which regulate cellular levels of oxidative stress (Kim and Byzova, 2014). Altered cell-cell and cell-matrix adhesion are hallmarks of EndMT, observed in both CCM protein-deficient cell culture models (Maddaluno et al, 2013) and human CCM lesions (Bravi et al, 2016), which also leads to the upregulation of a host of transcription factors, including KLFs that contribute to the mesenchymal phenotype, but also regulate -and are regulated by- oxidative stress (Chen et al, 2015, Zucker et al, 2014).…”

Section: Role Of Inflammation In Ccm Pathogenesismentioning

confidence: 99%

“…Nonetheless, increased expression of several pro-angiogenic growth factors have been found in human CCM lesions, including VEGF, PDGF, and TGF-β (Abe et al, 2009, Jung et al, 2003, Maiuri et al, 2006, Yildirim et al, 2010), and increased VEGF expression has also been measured in KRIT1 deficient animals (Corr et al, 2012). DiStefano et al showed that loss of KRIT1 increases VEGF expression by increasing nuclear β-catenin (DiStefano et al, 2014), where β-catenin stimulates transcription of VEGF (Glading and Ginsberg, 2010). The increase in VEGF expression leads to autocrine binding of VEGFR2 and subsequent activation of downstream angiogenic signaling pathways, suggesting that VEGF expression contributes to a feed-forward pathway promoting the CCM pathologic phenotype.…”

Section: Role Of Angiogenesis In Ccm Pathogenesismentioning

confidence: 99%

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Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

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110

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Graphical abstractTowards a unifying mechanism for CCM disease pathogenesis and treatment.CCM proteins play pleiotropic roles in distinct redox-sensitive pathways by modulating the fine-tuned crosstalk between redox signaling and autophagy. Effective autophagy removes ROS-generating cellular trash, including damaged mitochondria, to rejuvenate cell environment, thus serving a cytoprotective function for the maintenance of endothelial cell monolayer integrity and functionality and blood–brain barrier (BBB) stability even under adverse stress conditions. Loss-of-function of a CCM protein (e.g., KRIT1) causes defective autophagy and altered redox signaling, affecting BBB stability and sensitizing endothelial cells to local oxidative stress and inflammatory events, which may act as key pathogenic determinants of focal formation and progression of CCM lesions. The common capacity to modulate the interplay between autophagy and redox signaling reconciles the distinct pharmacological approaches proposed so far for CCM disease prevention and treatment.

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Section: Role Of Angiogenesis In Ccm Pathogenesismentioning

confidence: 68%

Section: Current Knowledge Of the Molecular Basis And Mechanisms Of Cmentioning

confidence: 99%

Section: Role Of Inflammation In Ccm Pathogenesismentioning

confidence: 99%

Section: Role Of Angiogenesis In Ccm Pathogenesismentioning

confidence: 99%

See 2 more Smart Citations

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Retta

Glading

2016

The International Journal of Biochemistry & Cell Biology

Self Cite

110

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“…In addition, the knockdown of CCM1 and CCM3 expression in cultured aortic and artery endothelial cells promotes β-catenin signaling (9,10), although no direct link with the in vivo model of the disease has been made. Activation of canonical Wnt/β-catenin signaling is critical for brain vascularization and acquisition, by the microvasculature, of blood-brain barrier properties (11)(12)(13).…”

mentioning

confidence: 99%

Sulindac metabolites decrease cerebrovascular malformations in CCM3 -knockout mice

Bravi

Rudini

Cuttano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

103

100

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Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.cerebral cavernous malformation | endothelial cells | β-catenin | sulindac metabolites | vascular pathology T he vascular malformations that characterize the disease known as cerebral cavernous malformation (CCM) are concentrated in the central nervous system, and they typically show multiple lumens and vascular leakage (1). These abnormalities can result in severe neurological symptoms, including hemorrhagic stroke (2), and, to date, the only possible therapy is surgery (3). In humans, loss-of-function mutations in any one of three independent genes known as cerebral cavernous malformation 1, 2, and 3 (CCM1, CCM2, and CCM3) are the cause of the genetic form of CCM (4). Similarly, in murine models, the vascular phenotype can be reproduced by endothelium-specific loss-of-function mutations of any one of these three CCM-linked genes (5-7).We have recently reported (7) that TGF-β/BMP signaling is activated after ablation of CCM1, CCM2, or CCM3 and induces endothelial-to-mesenchymal transition (EndMT) that plays a crucial role in the development of vascular malformations. Nevertheless, the sequence of signaling responses elicited by ablation of CCM genes still remains to be defined. Inhibitors of the TGF-β/BMP-signaling pathways reduce the number and size of the malformations, but not completely (7), suggesting that other signaling pathways may be implicated.The Wnt/β-catenin pathway, in synergy with TGF-β signaling (8), is responsible for the EndMT switch of endothelial cells giving rise to the heart cushion in the embryo. In addition, the knockdown of CCM1 and CCM3 expression in cultured aortic and artery endothelial cells promotes β-catenin signaling (9, 10), although no direct link with the in vivo model of the disease has been made. Activation of canonical Wnt/β-catenin signaling is critical for brain vascularization and acquisition, by the microvasculature, of blood-brain barr...

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A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

et al. 2018

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Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

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KRIT1 Protein Depletion Modifies Endothelial Cell Behavior via Increased Vascular Endothelial Growth Factor (VEGF) Signaling

Cited by 59 publications

References 70 publications

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

Sulindac metabolites decrease cerebrovascular malformations in CCM3 -knockout mice

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

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