Objective:
Cerebral cavernous malformations (CCM), consisting of dilated capillary channels formed by a single layer of endothelial cells lacking surrounding mural cells. It is unclear why CCM lesions are primarily confined to brain vasculature, although the 3 CCM-associated genes (
CCM1
,
CCM2
, and
CCM3
) are ubiquitously expressed in all tissues. We aimed to determine the role of
CCM
gene in brain mural cell in CCM pathogenesis.
Approach and Results:
SM22α
-Cre was used to drive a specific deletion of
Ccm3
in mural cells, including pericytes and smooth muscle cells (Ccm3smKO). Ccm3smKO mice developed CCM lesions in the brain with onset at neonatal stages. One-third of Ccm3smKO mice survived upto 6 weeks of age, exhibiting seizures, and severe brain hemorrhage. The early CCM lesions in Ccm3smKO neonates were loosely wrapped by mural cells, and adult Ccm3smKO mice had clustered and enlarged capillary channels (caverns) formed by a single layer of endothelium lacking mural cell coverage. Importantly, CCM lesions throughout the entire brain in Ccm3smKO mice, which more accurately mimicked human disease than the current endothelial cell-specific
CCM3
deletion models. Mechanistically,
CCM3
loss in brain pericytes dramatically increased paxillin stability and focal adhesion formation, enhancing ITG-β1 (integrin β1) activity and extracellular matrix adhesion but reducing cell migration and endothelial cell-pericyte associations. Moreover, CCM3-wild type, but not a paxillin-binding defective mutant, rescued the phenotypes in CCM3-deficient pericytes.
Conclusions:
Our data demonstrate for the first time that deletion of a
CCM
gene in the brain mural cell induces CCM pathogenesis.
Endothelial cell clonal expansion in the development of cerebral cavernous malformations