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The role of microvascular endothelial WNT signaling the formation of the blood brain barrier
- Source :
- SpringerPlus
- Publication Year :
- 2016
-
Abstract
- We analyzed the pathological consequences of abnormal Wnt/β-catenin signaling in endothelial cells of brain vessels using a murine model of Cerebral Cavernous Malformation (CCM) disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report increased transcription activity of β-catenin in CCM3-knockout endothelial cells in in-vitro and in-vivo models. Such activation is cell-autonomous, independent of Wnt-receptor stimulation, does not induce canonical Wnt/β-catenin signaling and represents an early response to CCM3 ablation that initiates the expression of EndMT makers before the onset of Tgf-β/BMP signaling which is required for the progression of the pathology, as we have previously described. We also show that the NSAIDs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, significantly reduce the number and dimension of vascular lesions in the central nervous system of mice with endothelial cell CCM3 knockout. These NSAIDs thus represent pharmacological tools for inhibition of the formation of vascular lesions, particularly with a view to patients affected by the genetic variant of CCM, who continue to develop new malformations over time.
- Subjects :
- Pathology
medicine.medical_specialty
Beta-catenin
Endothelium
endothelium
Central nervous system
Stimulation
Blood–brain barrier
Cerebral Cavernous Malformation
03 medical and health sciences
0302 clinical medicine
Transcription (biology)
medicine
030304 developmental biology
Lecture Presentation
0303 health sciences
Multidisciplinary
biology
Wnt signaling pathway
beta-catenin
3. Good health
Endothelial stem cell
medicine.anatomical_structure
biology.protein
Cancer research
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 21931801
- Volume :
- 4
- Issue :
- Suppl 1
- Database :
- OpenAIRE
- Journal :
- SpringerPlus
- Accession number :
- edsair.doi.dedup.....25c425d37f5ed6b37777130567c4e962