Endothelial estrogen receptor alpha (ESR1) regulates cerebral cavernous malformation pathogenesis via MEKK3–KLF signaling pathway

Cerebral cavernous malformations (CCMs) are common brain hemangioma that can occur sporadically or be inherited. CCM is one of the major causes of hemorrhagic stroke and neurological deficits in children. There are no pharmacological treatments for CCM. Clinical observations suggest that estrogen may have important roles in CCM, however, it has not been investigated. Hence, we investigated the role of estrogen and its nuclear receptors estrogen receptor-α (Esr1) in experimental CCM. To determine the role of endothelial ESR1 in CCM, we crossed homozygous endothelial Esr1 (Esr1^fl/fl) mice into Ccm1^iECKO mice. Micro-computed tomography (micro-CT) imaging was used to analyze CCM burden. To determine the therapeutic potential of estrogen, we treated Ccm1^iECKO mice with estradiol (E2, a clinically approved estrogen). Gene and protein expressions were assessed in human umbilical vein endothelial cells (HUVECs). Homozygous deletion of endothelial Esr1 in Ccm1^iECKO mice significantly increased CCM lesion volume compared to littermate controls. KLF2/4 and downstream expressions in HUVECs were further increased by ESR1 depletion. This correlated with increased lesion burden in Ccm1^iECKOEsr1^fl/fl mice. Furthermore, we demonstrated E2 treatment in Ccm1^iECKO mice prevented CCM pathogenesis by normalizing KLF2/4 and downstream expressions. Our study demonstrates ESR1 as a novel targeted therapeutic option for CCM.