Expression of retinoic acid pathway components is misregulated in in vitro and in vivo models of CCM. (a) Retinoic acid synthesis and degradation pathway. Synthesis of retinoic acid from Vitamin A (retinol) is dependent on availability of NADPH. In this study, all-trans RA and the Cyp26 inhibitor Talarozole were used to modulate RA levels. (b) Comparative expression levels of RA pathway genes in ccm2 mutant zebrafish hearts, pan-endothelial Ccm2 knock-out mouse veins, and siRNA CCM2-depleted HUVECs. Fold changes in expression levels are depicted in circle sizes (grouped by fold changes between 0 and 5, see legend). Downregulated transcripts are represented with blue circles whereas upregulated genes are shown in red circles. Transcripts not represented in the datasets do not contain a circle. Gene names are represented as human orthologs except for genes for which only co-orthologs are known (marked with asterisks). (c) Whole-mount in situ hybridization of raldh2 performed on 72 hpf old zebrafish and magnifications of the heart region (see box). Stained valve leaflets are marked by an arrow.
