The capillary-venous pathology
cerebral cavernous malformation (CCM) is caused by loss of CCM1/
Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of 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 in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with
retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of
retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the
retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying
retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when
retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were
drug regiment-sensitive, possibly due to adverse developmental effects of this
hormone. A treatment with high doses of
retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that
retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of
retinoic acid levels can alleviate CCM phenotypes.