Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition

Abstract

Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

“…Loss-of-function of CCM proteins has also been shown to trigger β-catenin and transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling-driven endothelial-to-mesenchymal transition (EndMT) (Bravi et al, 2016, Bravi et al, 2015, Guan and Couldwell, 2013, Maddaluno et al, 2013), as well as activation of MEKK3 signaling and increased expression of the mechanosensitive transcription factors KLF2 and KLF4 (Cullere et al, 2015, Cuttano et al, 2016, Fisher et al, 2015; Zhou et al, 2015; Zhou et al, 2016). Both of these mechanisms have been suggested to be key determinants of CCM disease pathogenesis (Maddaluno et al, 2013, Bravi et al, 2016, Cuttano et al, 2016, Zhou et al, 2016).…”

“…Both of these mechanisms have been suggested to be key determinants of CCM disease pathogenesis (Maddaluno et al, 2013, Bravi et al, 2016, Cuttano et al, 2016, Zhou et al, 2016). Moreover, it has been also suggested that increased Rho activity, as well as proteolytic activity of extracellular matrix metalloprotease ADAMTS, arises secondary to increased MEKK3–KLF2/4 signaling during CCM formation (Zhou et al, 2016).…”

“…These can then upregulate both pro-inflammatory and pro-angiogenic signals, such as VEGF expression (DiStefano et al, 2014), which regulate cellular levels of oxidative stress (Kim and Byzova, 2014). Altered cell-cell and cell-matrix adhesion are hallmarks of EndMT, observed in both CCM protein-deficient cell culture models (Maddaluno et al, 2013) and human CCM lesions (Bravi et al, 2016), which also leads to the upregulation of a host of transcription factors, including KLFs that contribute to the mesenchymal phenotype, but also regulate -and are regulated by- oxidative stress (Chen et al, 2015, Zucker et al, 2014). Recent attention has focused on the activation of MAP kinase signaling, particularly downstream of the scaffold MEKK3, which is activated in mouse models of CCM, and which binds to CCM2 (Fisher et al, 2015, Uhlik et al, 2003).…”

Cerebral Cavernous Malformations: Review of the Genetic and Protein–Protein Interactions Resulting in Disease Pathogenesis

“…Bravi et al also found that once this change occurred in the endothelial cells of CCMs, TGF-β/BMP signaling was subsequently required for the progression of the disease (48). The authors also found that this endothelial-to-mesenchymal cell transformation occurred in sporadic CCM lesions in addition to the familial and animal model lesions (49). While these findings are interesting from a pathogenic standpoint, they are even more intriguing because they suggest potential therapeutic options for the treatment and prevention of CCMs.…”

Cerebrovascular disorders associated with genetic lesions

“…Of all these bona fide interactors, MEKK3 [92, 93, 101-104], has emerged as a key player in the formation and progression of CCM lesions. Gain of MEKK3 signaling and upregulation of its targets, the transcription factors KLF2 and KLF4 have been causally linked to CCM pathogenesis and onset and progression of lesions [105-107], preceding endothelial-to-mesenchymal transition, underlain by changes in TGF-β/BMP signaling sensitivity [82, 108, 109]. Additional work will be needed to fully elucidate lesion formation at the cellular and molecular level.…”