UC San Diego

Cerebral Cavernous Malformations (CCMs) are common vascular disruptions occurring mainly in the brain and spinal cord in which chronic hemorrhage leads to neurological deficits, headaches, seizures, and sometimes death. The 3 genes known to cause CCM when mutated include Krit1 (Krev Interaction Trapped 1), CCM2, and PDCD10 (Programmed Cell Death 10, also known as CCM3). Heg1 (Heart of Glass) is a transmembrane protein known to recruit and anchor both Krit1 and Rasip1 (Ras Interacting Protein 1) to the membrane, maintaining vascular homeostasis by stabilizing endothelial cell-cell junctions. It has been shown that endothelial deficiency of Krit1, CCM2, or PDCD10 will lead to CCM lesion formation in various mouse models. Interestingly, although deletion of Heg1 alone does not lead to CCM development, when Heg1 is deleted in combination with Krit1, lesions formation is exacerbated. Our task was to find the potential pathways Heg1 is involved in that lead to the exacerbation of CCM lesion formation. Through in vivo and in vitro experiments, we found that when both Krit1 and Heg1 are depleted, lesion volume in mouse hindbrains increases, and Klf4 expression is drastically amplified in retinal endothelial cells. We found that Rasip1, an important Heg1 interactor, functions in the same pathway as Krit1 and Heg1. In addition, Mekk3 is important in the regulation of Klf2/4 expression, and knockdown of Mekk3 can rescue the increased Klf2/4 expression caused by Krit1/Heg1 knockdown. Further experiments are needed to better understand the role of Heg1 in the development of CCMs and elucidate the pathways involved.