Researchers have identified a “missing link” protein, TIE2, that drives the growth of dangerous blood vessel abnormalities in the brain. These abnormalities, known as cerebral cavernous malformations (CCMs), affect up to 1 in 200 people and can lead to strokes, seizures, and hemorrhages.
The study reveals that TIE2 acts as the bridge between two major signaling pathways (MEKK3 and PI3K) that cause these “mulberry-shaped” lesions to form. By targeting TIE2 with an existing oral drug, researchers successfully prevented new lesions in mice, offering a potential breakthrough for patients with inoperable brain malformations.
Key Facts
- The Mulberry Lesion: CCMs are fragile, thin-walled blood vessels that often require risky surgery if they become symptomatic or inoperable due to their location.
- TIE2 Discovery: TIE2 is a cell surface receptor that “boosts” the signals telling blood vessels to grow abnormally. It was found to be hyperactive in both human and mouse CCMs.
- Precision Medicine: Previously, doctors looked at blocking the PI3K pathway, but those drugs cause severe side effects because PI3K is vital for the whole body. Targeting TIE2 is “vessel-specific,” meaning it targets the problem without wrecking healthy tissues.
- The Drug (Rebastinib): An orally available drug called rebastinib successfully blocked TIE2 and stopped CCM development in animal models.
Source: Rockefeller University Press
Researchers in the Perelman School of Medicine at the University of Pennsylvania have identified a cell surface receptor protein called TIE2 as the missing link between two key signaling pathways that drive the growth of blood vessel abnormalities known as cerebral cavernous malformations (CCMs).
The study, to be published March 27 in the Journal of Experimental Medicine (JEM), suggests that drugs targeting TIE2 could be used to prevent the formation of CCMs, which, if left untreated, can cause brain hemorrhages, strokes, and seizures.
CCMs are mulberry-shaped vascular lesions that arise in the veins and venules of the central nervous system, resulting in fragile blood vessels with abnormally thin walls. They are usually caused by mutations in one of three genes.
These mutations can be inherited within families but can also arise spontaneously: CCMs may occur in as many as 1 in 200 people. Once detected, the only way to remove CCMs is by surgical resection but, in many cases, their location within the brain may render them inoperable.
CCM-causing mutations hyperactivate a signaling pathway, called the MEKK2-KLF2/4 pathway, in the endothelial cells that line blood vessel walls. Recent studies have shown that this hyperactivation stimulates a second signaling pathway involving the enzyme phosphoinositide 3-kinase (PI3K).
Drugs that inhibit the PI3K pathway can prevent the formation of CCMs in mice. But due to the vital importance of the PI3K pathway in many tissues of the body, these drugs have severe side effects in humans and may be poorly tolerated during long-term treatment of CCMs.
“Determining how endothelial cells augment PI3K signaling downstream of the MEKK3-KLF2/4 pathway could identify a more blood vessel–specific therapeutic strategy for chronic suppression of CCM growth,” says Mark L. Kahn, a professor at Penn, and senior author of the new JEM study. “However, the molecular mechanism by which augmented MEKK3-KLF2/4 function increases PI3K signaling has remained unclear.”
In the new study, Kahn and colleagues reveal that these two signaling pathways are linked by TIE2, a receptor protein on the surface of endothelial cells that regulates blood vessel development.
The researchers found that TIE2 activity was enhanced in the endothelial cells surrounding both human and mouse CCMs. Levels of the TIE2 protein are increased in response to elevated MEKK3-KLF2/4 signaling, and this, in turn, leads to increased activation of the PI3K pathway. Crucially, Kahn and colleagues found that inhibiting TIE2 with a small, orally available drug called rebastinib prevented the development of new CCMs in mice.
“Our findings identify TIE2 as a crucial link between the MEKK3-KLF2/4 and PI3K signaling pathways, and suggest that pharmacologic blockade of TIE2 may provide an endothelial cell–centered approach for chronic suppression of CCM disease with fewer side effects than systemic PI3K pathway inhibition,” Kahn says.
Key Questions Answered:
A: Imagine a tiny, fragile bunch of grapes made of blood vessels. Because the walls are so thin, they leak blood into the surrounding brain tissue. This “leakiness” is what triggers seizures or, in worse cases, a full hemorrhagic stroke.
A: We tried! But the main “growth switch” (PI3K) is used by almost every cell in your body. Turning it off is like turning off the electricity in your whole house just to fix one flickering lightbulb. This new discovery of TIE2 is like finding the specific light switch for that one bulb.
A: While surgical removal is still the standard for existing large lesions, this drug approach is designed for suppression. It could stop small, “quiet” malformations from growing into dangerous ones and prevent new ones from forming in families with a genetic predisposition.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurology research news
Author: Ben Short
Source: Rockefeller University Press
Contact: Ben Short – Rockefeller University Press
Image: The image is credited to Neuroscience News
Original Research: Open access.
“TIE2 links MEKK3–KLF2/4 and PI3K signaling in cerebral cavernous malformation” by 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, and Mark L. Kahn. Journal of Experimental Medicine
DOI:10.1084/jem.20251374
Abstract
TIE2 links MEKK3–KLF2/4 and PI3K signaling in cerebral cavernous malformation
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.
