Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non‐invasive pharmacological therapies. Here, we present the results of several unbiased small‐molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology‐based target prediction tool to integrate the results with the whole‐transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small‐molecule‐based therapies. We found indirubin‐3‐monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss‐of‐CCM phenotypes in human endothelial cells. Our multi‐organism‐based approach reveals new components of the CCM regulatory network and foreshadows novel small‐molecule‐based therapeutic applications for suppressing this devastating disease in patients.
Highlights
Cerebral cavernous malformations are characterized by the presence of vascular lesions that are most prevalent in the brain and can occur sporadically or through a familial condition from mutations in CCM1/KRIT1, CCM2/Malcavernin, or CCM3/PDCD10 [reviewed in (Chan et al, 2010; Riant et al, 2010; Fischer et al, 2013)]
To assess whether additional genes related to disease-relevant genetic pathways might be affected, we carried out comparative Gene Ontology biological process (GO-BP) term analyses based on the zebrafish DePick dataset and found that only two GO-BP terms were significant for the zebrafish ccm2m201 mutant cardiac tissue dataset (Ashburner et al, 2000; The Gene Ontology Consortium, 2017): In line with evidence from several functional studies, our analyses indicate that VEGF-dependent angiogenesis signaling is relevant to the disease (Wustehube et al, 2010; Zhu et al, 2010; You et al, 2013; Renz et al, 2015; Lopez-Ramirez et al, 2017), as well as retinoic acid signaling since several of these genes cluster under the GO-BP term “anatomical structure morphogenesis” (Fig 2; Dataset EV4)
We found that treatment with IR3mo a 2018 The Authors had no effect on the width of the cerebellum (Fig 5E) and on the animal weight (Fig 5F) of the iCCM2 mice at P8
Summary
Cerebral cavernous malformations are characterized by the presence of vascular lesions that are most prevalent in the brain and can occur sporadically or through a familial condition from mutations in CCM1/KRIT1, CCM2/Malcavernin, or CCM3/PDCD10 [reviewed in (Chan et al, 2010; Riant et al, 2010; Fischer et al, 2013)]. Loss of CCM proteins in Caenorhabditis elegans, zebrafish, and mouse leads to penetrant defects in vascular structures and conserved signaling pathways. These model organisms offer many advantages for suppressing these phenotypes using small molecules or genetic methods. Loss of any of the Ccm proteins in zebrafish and mouse causes cardiovascular malformations that result in cardiac defects, including abnormal cardiac chamber ballooning, a failure of endocardial cushions to form at the atrioventricular canal, and defects in blood vessel formation (Mably et al, 2003, 2006; Hogan et al, 2008; Boulday et al, 2009; Kleaveland et al, 2009; Zheng et al, 2010; Yoruk et al, 2012; Renz et al, 2015; Zhou et al, 2015). The endothelial-specific deletion of Ccm at postnatal day 1 leads to lesions in the CNS and retinal vasculature which resemble CCM lesions in patients (Boulday et al, 2011)
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