Impaired retinoic acid signaling in cerebral cavernous malformations

International audienceThe capillary-venous pathology cerebral cavernous malormation (CCM) is caused by loss o CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations o CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and inoperable regions o the central nervous system. Previous pharmacological suppression screens in disease models o CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This nding raised a need to investigate the involvement o retinoic acid in CCM and test whether it has a curative eect in preclinical mouse models. Here, we show that components o the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models o CCM. We complemented this analysis by pharmacologically modiying retinoic acid levels in zebrash and human endothelial cell models o CCM, and in acute and chronic mouse models o CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrash showed positive eects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development o vascular lesions in adult chronic murine models o CCM were drug regiment-sensitive, possibly due to adverse developmental eects o this hormone. A treatment with high doses o retinoic acid even worsened CCM lesions in an adult chronic murine model o CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modication o retinoic acid levels can alleviate CCM phenotypes

Circulating biomarkers in familial cerebral cavernous malformation

Background Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression.Methods Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n =17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches.Findings Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM.Interpretation Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease