Cerebral cavernous malformations (CCMs) are common brain lesions formed by abnormally dilated and leaky blood vessels that can hemorrhage and cause strokes and seizures. The lesions are associated with defects in the adhesions that connect vascular endothelial cells, but Faurobert et al. reveal that CCMs are aggravated by aberrant cell–extracellular matrix interactions (1).

CCMs can be caused by mutations in the genes encoding three proteins known as CCM1, 2, and 3. CCM1 and CCM2 form a complex that promotes the formation of VE-cadherin–based adherens junctions between endothelial cells (2). In the absence of these proteins, the RhoA GTPase and its effector ROCK increase cellular contractility and disrupt endothelial junctions, thereby increasing vascular permeability (3). But CCM proteins may also regulate the integrin-based focal adhesions that connect endothelial cells to the underlying extracellular matrix. The basal lamina surrounding vascular endothelial cells is disorganized in CCMs (4), and the CCM1 protein binds to ICAP-1, a protein that inhibits β1 integrin by binding to its cytoplasmic tail (5). “Because of this, we wondered whether the CCM complex controls integrin signaling and cell–extracellular matrix interactions,” says Corinne Albiges-Rizo, from the Institut Albert Bonniot in Grenoble, France.

Albiges-Rizo and colleagues, led by Eva Faurobert, found that binding to the CCM complex stabilized ICAP-1 so that, in endothelial cells lacking CCM1 or CCM2, levels of the β1 integrin inhibitor were also greatly reduced (1). “This releases the inhibition of β1 integrin, leading to the appearance of numerous focal adhesions all over the ventral surface of the cells,” explains Faurobert. “This is different to control endothelial cells, where focal adhesions only form in the cell periphery.”

“The matrix itself was enough to transmit a mutant-like phenotype.”

Because β1 integrin–based adhesion can activate RhoA and ROCK, Faurobert et al. wondered whether the loss of ICAP-1 might cause the increased contractility and adherens junction defects seen in CCM-deficient cells. Sure enough, knocking down ICAP-1 increased RhoA activity and actin stress fiber formation in endothelial cells while decreasing the assembly of adherens junctions. Knocking down β1 integrin reversed this phenotype in both ICAP-1– and CCM-deficient cells.

Faurobert et al. thought that the loss of ICAP-1 might have effects outside the cell as well. Actomyosin contractility can be propagated through focal adhesions to remodel fibronectin in the extracellular matrix. The researchers therefore investigated whether the increase in focal adhesion formation and contractility following CCM or ICAP-1 depletion would affect how endothelial cells reorganize fibronectin matrices in vitro. “Control cells wove the fibronectin matrix together like a fabric,” says Faurobert, “but the mutant cells remodeled fibronectin into parallel, linear fibers. So the geometry of fibronectin was totally different and probably increases the rigidity of the extracellular matrix.”

The extracellular matrix was similarly disorganized around the malformed blood vessels of CCM- and ICAP-1–deficient mice. Moreover, the researchers found that the alterations in fibronectin geometry and rigidity feed back to enhance the contractility of endothelial cells still further. To demonstrate this, Faurobert et al. seeded wild-type cells onto fibronectin matrices already remodeled by CCM-deficient cells. “The matrix itself was enough to transmit a mutant-like phenotype to wild-type cells,” Faurobert explains. “They became more contractile, expressed more stress fibers, and reduced the formation of cell–cell junctions.”

ICAP-1 and the CCM complex therefore regulate the mechanical process linking cell–extracellular matrix interactions to intercellular adhesions and vascular permeability. “People talk about the cross talk between integrins and cadherins, but the pathways aren’t known,” Albiges-Rizo says. “We’ve identified the CCM complex as a node orchestrating cadherin-dependent and integrin-dependent cell adhesion.”

The findings suggest new approaches to treating CCMs. Inhibitors of active β1 integrin, for example, which are already in clinical trials as anti-cancer agents, could be tested for their effects on CCM-knockout mice. Faurobert and Albiges-Rizo, meanwhile, plan to investigate in more detail how the CCM complex regulates the distribution of forces between intercellular and cell–matrix adhesions.

References

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Author notes

Text by Ben Short