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Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3\u2013KLF2\/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two\u00a0mouse 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\u2013KLF2\/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\u2013KLF2\/4 and PI3K signaling pathways during CCM formation and suggest that targeting TIE2 may be an effective means to treat human CCM disease.<\/jats:p>","DOI":"10.1084\/jem.20251374","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:04:59Z","timestamp":1774620299000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["TIE2 links MEKK3\u2013KLF2\/4 and PI3K signaling in cerebral cavernous malformation"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2697-8296","authenticated-orcid":true,"given":"Lun","family":"Li","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Perelman School of Medicine, University of Pennsylvania 1 Cardiovascular Institute and Department of Medicine, , Philadelphia, 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