Lun Li, Marco Castro, Hiroki Hongo, Jian Ren, Robert Shenkar, Rashad Jabarkheel, Siqi Gao, Sweta Narayan, Maxwell Frankfurter, Alan T. Tang, Jisheng Yang, Mei Chen, Jenna Bockman, Patricia Mericko-Ishizuka, Roberto Alcazar, Georgio Sader, Javed Iqbal, Serena Kinkade, Rhonda Lightle, Andrew K. Ressler, Xianghu Qu, H. Scott Baldwin, Douglas A. Marchuk, Issam A. Awad, Jan-Karl Burkhardt, Michael Potente, Mark L. Kahn
Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary human endothelial cells to examine the roles of the major endothelial growth factor receptors, VEGFR2 and TIE2. We find no evidence of augmented VEGFR2 signaling in CCM lesions, and neither genetic nor pharmacologic blockade of VEGFR2 reduced CCM formation in mouse models. Instead, we observe markedly increased phospho-TIE2 levels in human and mouse CCM lesions, MEKK3-KLF2/4-driven induction of TIE2 receptor expression, and almost complete rescue of CCM formation following genetic or pharmacologic TIE2 blockade in mouse models. Our studies identify TIE2 as the molecular link between the MEKK3-KLF2/4 and PI3K signaling pathways during CCM formation and suggest that targeting TIE2 may be an effective means to treat human CCM disease.