scholarly journals Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations

2017 ◽  
Vol 214 (11) ◽  
pp. 3331-3346 ◽  
Author(s):  
Miguel Alejandro Lopez-Ramirez ◽  
Gregory Fonseca ◽  
Hussein A. Zeineddine ◽  
Romuald Girard ◽  
Thomas Moore ◽  
...  
Keyword(s):  
Cavernous Malformation ◽  
Angiogenesis Inhibitors ◽  
Cerebral Cavernous Malformations ◽  
Growth Factor Signaling ◽  
Vascular Endothelial ◽  
Micro Computed Tomography ◽  
Cavernous Malformations ◽  
In Vitro Reconstitution ◽  
Endothelial Growth Factor

KRIT1 mutations are the most common cause of cerebral cavernous malformation (CCM). Acute Krit1 gene inactivation in mouse brain microvascular endothelial cells (BMECs) changes expression of multiple genes involved in vascular development. These changes include suppression of Thbs1, which encodes thrombospondin1 (TSP1) and has been ascribed to KLF2- and KLF4-mediated repression of Thbs1. In vitro reconstitution of TSP1 with either full-length TSP1 or 3TSR, an anti-angiogenic TSP1 fragment, suppresses heightened vascular endothelial growth factor signaling and preserves BMEC tight junctions. Furthermore, administration of 3TSR prevents the development of lesions in a mouse model of CCM1 (Krit1ECKO) as judged by histology and quantitative micro-computed tomography. Conversely, reduced TSP1 expression contributes to the pathogenesis of CCM, because inactivation of one or two copies of Thbs1 exacerbated CCM formation. Thus, loss of Krit1 function disables an angiogenic checkpoint to enable CCM formation. These results suggest that 3TSR, or other angiogenesis inhibitors, can be repurposed for TSP1 replacement therapy for CCMs.

scholarly journals The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3

2015 ◽  
Vol 112 (46) ◽  
pp. 14284-14289 ◽  
Author(s):  
Xavier Cullere ◽  
Eva Plovie ◽  
Paul M. Bennett ◽  
Calum A. MacRae ◽  
Tanya N. Mayadas
Keyword(s):  
Endothelial Cells ◽  
Cavernous Malformation ◽  
Body Axis ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
Downstream Target ◽  
Density Flow

Three genes, CCM1, CCM2, and CCM3, interact genetically and biochemically and are mutated in cerebral cavernous malformations (CCM). A recently described member of this CCM family of proteins, CCM2-like (CCM2L), has high homology to CCM2. Here we show that its relative expression in different tissues differs from that of CCM2 and, unlike CCM2, the expression of CCM2L in endothelial cells is regulated by density, flow, and statins. In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1. Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target. The in vivo relevance of this regulation was investigated in zebrafish. A knockdown of ccm2l and ccm2 in zebrafish leads to a more severe “big heart” and circulation defects compared with loss of function of ccm2 alone, and also leads to substantial body axis abnormalities. Silencing of mekk3 rescues the big heart and body axis phenotype, suggesting cross-talk between the CCM proteins and MEKK3 in vivo. In endothelial cells, CCM2 deletion leads to activation of ERK5 and a transcriptional program that are downstream of MEKK3. These findings suggest that CCM2L and CCM2 cooperate to regulate the activity of MEKK3.

scholarly journals Cerebral Cavernous Malformation: From Mechanism to Therapy

2021 ◽  
Vol 129 (1) ◽  
pp. 195-215
Author(s):  
Daniel A. Snellings ◽  
Courtney C. Hong ◽  
Aileen A. Ren ◽  
Miguel A. Lopez-Ramirez ◽  
Romuald Girard ◽  
...  
Keyword(s):  
Complex Disease ◽  
Vascular Endothelial Cells ◽  
Cavernous Malformation ◽  
Clinical Investigation ◽  
Cerebral Cavernous Malformation ◽  
Cerebral Cavernous Malformations ◽  
Vascular Endothelial ◽  
Molecular Signaling ◽  
Genetic Studies ◽  
Cavernous Malformations

Cerebral cavernous malformations are acquired vascular anomalies that constitute a common cause of central nervous system hemorrhage and stroke. The past 2 decades have seen a remarkable increase in our understanding of the pathogenesis of this vascular disease. This new knowledge spans genetic causes of sporadic and familial forms of the disease, molecular signaling changes in vascular endothelial cells that underlie the disease, unexpectedly strong environmental effects on disease pathogenesis, and drivers of disease end points such as hemorrhage. These novel insights are the integrated product of human clinical studies, human genetic studies, studies in mouse and zebrafish genetic models, and basic molecular and cellular studies. This review addresses the genetic and molecular underpinnings of cerebral cavernous malformation disease, the mechanisms that lead to lesion hemorrhage, and emerging biomarkers and therapies for clinical treatment of cerebral cavernous malformation disease. It may also serve as an example for how focused basic and clinical investigation and emerging technologies can rapidly unravel a complex disease mechanism.

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