Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis

Fischer, Andreas; Zalvide, Juan; Faurobert, Eva; Albiges-Rizo, Corinne; Tournier‐Lasserve, Elisabeth

doi:10.1016/j.molmed.2013.02.004

Cited by 169 publications

(153 citation statements)

References 70 publications

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…Mouse genetic studies have shown that all three CCM proteins are required for embryonic and postnatal cardiovascular development (111). Clinical features of the disease and the biochemistry of the proteins and their interactions have been reviewed previously (112). Dilated vessels with low flow will have even lower shear stress due to the inverse dependence of FSS on vessel diameter, raising the question of how the normal homeostatic control of vessel diameter is circumvented in CCM.…”

Section: Plaque Progression and Remodelingmentioning

confidence: 99%

Endothelial fluid shear stress sensing in vascular health and disease

Baeyens

Bandyopadhyay

Coon

et al. 2016

Journal of Clinical Investigation

452

407

View full text Add to dashboard Cite

Section: Plaque Progression and Remodelingmentioning

confidence: 99%

Endothelial fluid shear stress sensing in vascular health and disease

Baeyens

Bandyopadhyay

Coon

et al. 2016

Journal of Clinical Investigation

452

407

View full text Add to dashboard Cite

“…CCM lesions consist of a mulberry-like cluster of enlarged and irregular blood vessels surrounded by a thick, multilayered basal membrane. 1,2 The endothelial channels have poorly developed tight and adherens junctions, and are rarely covered by pericytes, astrocytes, or vascular smooth muscle cells (VSMCs). [3][4][5] Growth and bleeding of CCM lesions cause neurological defects, such as pharmacorefractory epilepsy, migraine-like headaches, focal neurological deficits, and hemorrhages.…”

mentioning

confidence: 99%

“…[3][4][5] Growth and bleeding of CCM lesions cause neurological defects, such as pharmacorefractory epilepsy, migraine-like headaches, focal neurological deficits, and hemorrhages. 1,2 CCM is caused by loss-of-function mutations in the CCM1 (KRIT1), CCM2 (OSM), and CCM3 (PDCD10) genes. The detailed pathobiology is still not understood.…”

mentioning

confidence: 99%

Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes

Schulz

Wieland

Wüstehube-Lausch

et al. 2015

Stroke

Self Cite

View full text Add to dashboard Cite

Background and Purpose— Cerebral cavernous malformation (CCM) is a neurovascular dysplasia characterized by conglomerates of enlarged endothelial channels in the central nervous system, which are almost devoid of pericytes or smooth muscle cells. This disease is caused by loss-of-function mutations in CCM1 , CCM2 , or CCM3 genes in endothelial cells, making blood vessels highly susceptible to angiogenic stimuli. CCM1 - and CCM3 -silenced endothelial cells have a reduced expression of the Notch ligand Delta-like 4 (DLL4) resulting in impaired Notch signaling and irregular sprouting angiogenesis. This study aimed to address if DLL4, which is exclusively expressed on endothelial cells, may influence interactions of endothelial cells with pericytes, which express Notch3 as the predominant Notch receptor. Methods— Genetic manipulation of primary human endothelial cells and brain pericytes. Transgenic mouse models were also used. Results— Endothelial cell–specific ablation of Ccm1 and Ccm2 in different mouse models led to the formation of CCM-like lesions, which were poorly covered by periendothelial cells. CCM1 silencing in endothelial cells caused decreased Notch3 activity in cocultured pericytes. DLL4 proteins stimulated Notch3 receptors on human brain pericytes. Active Notch3 induced expression of PDGFRB2, N-Cadherin , HBEGF , TGFB1, NG2 , and S1P genes. Notch3 signaling in pericytes enhanced the adhesion strength of pericytes to endothelial cells, limited their migratory and invasive behavior, and enhanced their antiangiogenic function. Pericytes silenced for Notch3 expression were more motile and could not efficiently repress angiogenesis. Conclusions— The data suggest that Notch signaling in pericytes is important to maintain the quiescent vascular phenotype. Deregulated Notch signaling may, therefore, contribute to the pathogenesis of CCM.

show abstract

“…Cerebral cavernous malformations (CCMs) consist of clusters of enlarged endothelial channels ('caverns') that are arranged backto-back to form densely packed sinusoids with little or no intervening brain parenchyma (reviewed in Cavalcanti et al, 2012;Fischer et al, 2013). These lesions lack smooth muscle and elastic tissue, so the vessel walls are thin, leaky and lack sub-endothelial support and an intact basal lamina.…”

Section: Introductionmentioning

confidence: 99%

“…CCMs have been reported in up to 0.5% of the population and, although they are primarily found within the neurovasculature of the central nervous system (i.e. brain, spinal cord, retina), where they result in increased risk for stroke, seizures and focal neurological deficits, they are also seen in the skin and liver (Cavalcanti et al, 2012;Fischer et al, 2013). Currently, the only treatment for CCM is surgical resection.…”

Section: Introductionmentioning

confidence: 99%

Cerebral cavernous malformation proteins at a glance

Draheim

Fisher

Boggon

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of current models of CCM protein function focusing on how known protein-protein interactions might contribute to cellular phenotypes and highlighting gaps in our current understanding.

show abstract

Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis

Cited by 169 publications

References 70 publications

Endothelial fluid shear stress sensing in vascular health and disease

Endothelial fluid shear stress sensing in vascular health and disease

Cerebral Cavernous Malformation-1 Protein Controls DLL4-Notch3 Signaling Between the Endothelium and Pericytes

Cerebral cavernous malformation proteins at a glance

Contact Info

Product

Resources

About