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Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
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Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations
Miguel Alejandro Lopez-Ramirez1, Gregory Fonseca2, Hussein A Zeineddine3
1Department of Medicine, University of California, San Diego, La Jolla, CA.
The Journal of Experimental Medicine
|October 4, 2017
Summary
Loss of KRIT1 function in cerebral cavernous malformation (CCM) disables an angiogenic checkpoint. Thrombospondin1 (TSP1) replacement therapy, using TSP1 fragments like 3TSR, shows promise for treating CCM.
Area of Science:
- Biomedical research
- Vascular biology
- Genetics
Background:
- KRIT1 mutations are the primary cause of cerebral cavernous malformation (CCM).
- KRIT1 gene inactivation impacts genes regulating vascular development, including suppression of thrombospondin1 (TSP1).
Purpose of the Study:
- To investigate the role of TSP1 in CCM pathogenesis and evaluate TSP1-based therapies.
- To determine if TSP1 replacement can prevent or treat CCM lesions.
Main Methods:
- Studied gene expression changes in mouse brain microvascular endothelial cells (BMECs) after KRIT1 inactivation.
- Utilized in vitro reconstitution with full-length TSP1 or 3TSR (a TSP1 fragment).
- Administered 3TSR in a mouse model of CCM1 and assessed lesion development via histology and micro-computed tomography.
Main Results:
- KRIT1 inactivation suppressed TSP1 expression, mediated by KLF2/KLF4.
- TSP1 reconstitution (full-length or 3TSR) suppressed vascular endothelial growth factor signaling and preserved BMEC tight junctions.
- 3TSR administration prevented CCM lesion development in mice; reduced TSP1 exacerbated CCM formation.
Conclusions:
- Loss of KRIT1 function disrupts an angiogenic checkpoint, facilitating CCM formation.
- TSP1 replacement therapy, potentially using 3TSR, is a viable therapeutic strategy for CCMs.
