Drugs targeting TIE2 protein could help prevent formation of cerebral cavernous malformations

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. However, the molecular mechanism by which augmented MEKK3-KLF2/4 function increases PI3K signaling has remained unclear."

Mark L. Kahn, professor at Penn, and senior author of the new JEM study

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.