TY - JOUR
T1 - Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition
AU - Bravi, Luca
AU - Malinverno, Matteo
AU - Pisati, Federica
AU - Rudini, Noemi
AU - Cuttano, Roberto
AU - Pallini, Roberto
AU - Martini, Maurizio
AU - Larocca, Luigi Maria
AU - Locatelli, Marco
AU - Levi, Vincenzo
AU - Bertani, Giulio Andrea
AU - Dejana, Elisabetta
AU - Lampugnani, Maria Grazia
PY - 2016
Y1 - 2016
N2 - Background and Purpose-Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy. Methods-We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control. Results-We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad-and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones. Conclusions-Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.
AB - Background and Purpose-Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy. Methods-We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control. Results-We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad-and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones. Conclusions-Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.
KW - Adolescent
KW - Adult
KW - Advanced and Specialized Nursing
KW - Aged
KW - CCM
KW - Cardiology and Cardiovascular Medicine
KW - Central Nervous System Neoplasms
KW - Child
KW - EndMT
KW - Endothelium, Vascular
KW - Epithelial-Mesenchymal Transition
KW - Female
KW - Hemangioma, Cavernous, Central Nervous System
KW - Humans
KW - Male
KW - Middle Aged
KW - Neurology (clinical)
KW - Young Adult
KW - endothelium
KW - immunohistochemistry
KW - intracranial hemorrhage
KW - Adolescent
KW - Adult
KW - Advanced and Specialized Nursing
KW - Aged
KW - CCM
KW - Cardiology and Cardiovascular Medicine
KW - Central Nervous System Neoplasms
KW - Child
KW - EndMT
KW - Endothelium, Vascular
KW - Epithelial-Mesenchymal Transition
KW - Female
KW - Hemangioma, Cavernous, Central Nervous System
KW - Humans
KW - Male
KW - Middle Aged
KW - Neurology (clinical)
KW - Young Adult
KW - endothelium
KW - immunohistochemistry
KW - intracranial hemorrhage
UR - http://hdl.handle.net/10807/91847
UR - http://stroke.ahajournals.org/
U2 - 10.1161/STROKEAHA.115.011867
DO - 10.1161/STROKEAHA.115.011867
M3 - Article
SN - 0039-2499
VL - 47
SP - 886
EP - 890
JO - Stroke
JF - Stroke
ER -