Loss of CCM3 impairs DLL4‐Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. Issue 3 (7th February 2013)

• Record Type: Journal Article
• Authors: You, Chao; Erol Sandalcioglu, Ibrahim; Dammann, Philipp; Felbor, Ute; Sure, Ulrich; Zhu, Yuan
• Is Part Of: Journal of cellular and molecular medicine. Volume 17:Issue 3(2013)
• Page Start: 407
• Page End: 418
• Publication Date: 2013-02-07
• Subjects: Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.12022
• Languages: English
• ISSNs: 1582-1838

Abstract

<abstract abstract-type="main" id="jcmm12022-abs-0001"> <title>Abstract</title> <p>CCM3, a product of the <italic>cerebral cavernous malformation 3</italic> or <italic>programmed cell death 10</italic> gene <italic>(CCM3/PDCD10)</italic>, is broadly expressed throughout development in both vertebrates and invertebrates. Increasing evidence indicates a crucial role of CCM3 in vascular development and in regulation of angiogenesis and apoptosis. Furthermore, loss of CCM3 causes inherited (familial) cerebral cavernous malformation (CCM), a common brain vascular anomaly involving aberrant angiogenesis. This study focused on signalling pathways underlying the angiogenic functions of CCM3. Silencing <italic>CCM3</italic> by siRNA stimulated endothelial proliferation, migration and sprouting accompanied by significant downregulation of the core components of Notch signalling including <italic>DLL4, Notch4, HEY2</italic> and <italic>HES1</italic> and by activation of VEGF and Erk pathways. Treatment with recombinant DLL4 (rhDLL4) restored DLL4 expression and reversed <italic>CCM3</italic>‐silence‐mediated impairment of Notch signalling and reduced the ratio of <italic>VEGF‐R2</italic> to <italic>VEGF‐R1</italic> expression. Importantly, restoration of DLL4‐Notch signalling entirely rescued the hyper‐angiogenic phenotype induced by <italic>CCM3</italic> silence. A concomitant loss of <italic>CCM3</italic> and the core components of DLL4‐Notch signalling were also demonstrated in <italic>CCM3</italic>‐deficient endothelial cells derived from human CCM lesions (CCMEC) and in a <italic>CCM3</italic> germline mutation carrier. This study defined DLL4 as a key downstream target of CCM3 in endothelial cells. CCM3/DLL4‐Notch pathway serves as an important signalling for endothelial angiogenesis and is potentially implicated in the pathomechanism of human CCMs.</p> </abstract>