Researchers at the Perelman School of Medicine, University of Pennsylvania, have identified a critical receptor protein, TIE2, that connects two major signaling pathways and drives the formation of dangerous brain vascular lesions called cerebral cavernous malformations (CCMs). CCMs affect as many as 1 in 200 people and can cause seizures, hemorrhagic strokes, and long-term neurological problems. The new findings point to a vessel-specific therapeutic target that may prevent lesion growth with fewer side effects than broad-spectrum treatments.
Key Facts
- The Lesion: CCMs form mulberry-shaped clusters of fragile, thin-walled blood vessels in the brain and spinal cord. Because of their delicate structure and sometimes deep location, many CCMs are difficult or impossible to remove surgically.
- TIE2 Identified: TIE2 is a cell-surface receptor on endothelial cells that the team found to be upregulated and hyperactivated in both human and mouse CCM lesions. TIE2 links upstream MEKK3–KLF2/4 signaling with downstream PI3K activation.
- Precision Approach: Previous efforts targeted the PI3K pathway to block lesion growth, but systemic PI3K inhibitors produce serious side effects because PI3K is essential in many tissues. Targeting TIE2 offers a more vessel-focused strategy that could limit off-target toxicity.
- Drug Candidate: The orally available kinase inhibitor rebastinib blocked TIE2 activity in preclinical models and prevented formation of new CCMs in mice, supporting further investigation of TIE2-directed therapies.
The research, published in the Journal of Experimental Medicine, explains how mutations that cause CCMs hyperactivate an endothelial signaling cascade (MEKK3–KLF2/4). This hyperactivation in turn enhances PI3K signaling, promoting abnormal vessel growth and lesion formation. Until now, the molecular link between the MEKK3–KLF2/4 and PI3K pathways remained unclear. The new study demonstrates that TIE2 serves as that missing molecular link.
Using human CCM tissue samples, two mouse models of CCM disease, and primary human endothelial cells, the investigators studied the roles of major endothelial growth factor receptors. They found no evidence that VEGFR2 signaling is augmented in CCM lesions, and blocking VEGFR2 did not reduce lesion formation in mice. In contrast, phosphorylated (activated) TIE2 levels were markedly increased in both human and mouse CCMs.
Mechanistically, enhanced MEKK3–KLF2/4 signaling increases TIE2 receptor expression on endothelial cells, which then amplifies PI3K pathway activity. In mouse models, genetically reducing TIE2 function or pharmacologically inhibiting it with rebastinib nearly abolished new CCM formation. These results identify TIE2 as the molecular bridge converting MEKK3–KLF2/4 activation into pathogenic PI3K signaling during CCM development.
Mark L. Kahn, senior author of the study, notes that TIE2 inhibition represents an endothelial cell–centered approach to suppress CCM disease over the long term. Because TIE2 targeting is more vessel-specific than PI3K inhibition, it may offer effective chronic suppression of lesion growth with fewer systemic adverse effects.
Key Questions Answered
A: These lesions look like small clusters of fragile blood vessels—similar to a tiny bunch of grapes. The vessel walls are thin and prone to leaking blood into adjacent brain tissue, which can trigger seizures or, in severe cases, an intracerebral hemorrhage.
A: Prior strategies focused on inhibiting PI3K, a signaling enzyme that drives lesion growth. Because PI3K is essential across many organs, inhibiting it systemically causes serious side effects. Targeting TIE2 offers a narrower, vessel-focused intervention that may avoid those problems.
A: Surgical removal remains the definitive treatment for accessible, symptomatic lesions. The TIE2-targeting approach is intended primarily as suppression—to prevent small, asymptomatic or new lesions from enlarging and to reduce formation of lesions in people with a genetic predisposition.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context and clarifications were added by the newsroom team.
About this neurology research news
Author: Ben Short
Source: Rockefeller University Press
Contact: Ben Short – Rockefeller University Press
Image credit: Neuroscience News
Original Research: Open access. “TIE2 links MEKK3–KLF2/4 and PI3K signaling in cerebral cavernous malformation” by Lun Li et al., Journal of Experimental Medicine. DOI: 10.1084/jem.20251374
Abstract (summary)
Cerebral cavernous malformations are vascular lesions in the central nervous system that can produce strokes and seizures. Aggressive CCM growth results from an endothelial cell two-hit mechanism: increased MEKK3–KLF2/4 signaling stimulates PI3K activity, yet the molecular connection between these pathways was previously undefined. Using human lesion samples, two mouse models, and primary human endothelial cells, the study finds no role for augmented VEGFR2 signaling. Instead, MEKK3–KLF2/4 signaling drives upregulation and activation of TIE2, which in turn promotes PI3K pathway activation. Genetic or pharmacologic blockade of TIE2 markedly reduces CCM formation in mice. These results highlight TIE2 as a specific molecular link and a promising therapeutic target for preventing CCM growth while minimizing systemic toxicity.