Vascular Development Gene Helps Protect Against Stroke Damage

Variants of the human version of the gene may help explain why people differ so much in their ability to survive artery blockages.

The discovery, by researchers at the University of North Carolina Health Care System’s (Chapel Hill, NC, USA) school of medicine, provides a major clue towards understanding why some people sustain relatively little damage from strokes or heart attacks despite severe arterial blockages. When an artery is blocked, the damage to tissues downstream is often limited because these tissues continue to be nourished by special “collateral” vessels that connect the tissue to other arteries. However, for reasons that haven’t been understood, the number and size of these collateral vessels – and thus the protection they afford – can vary greatly between individuals.

The new study has implicated the Rabep2 gene as a major contributor to this variation in collateral vessel formation. The research team, led by James Faber, PhD, professor at UNC School of Medicine, found that variants of this gene account for most of the differences in collateral vasculature among laboratory mice. The human version of Rabep2 is likely to have a comparable function.

The scientists hope that one day doctors will be able to use a simple blood test to detect variants of the human form of the gene and that this would help doctors quickly gauge the extent of collateral vessels in patients who experience heart attacks, strokes, peripheral artery disease, and occlusive disorders in other tissues.

“Whether patients have good or poor collaterals strongly influences the severity of tissue injury after an occlusion and affects doctors’ decisions about how to treat patients or prescribe preventive measures,” said Prof. Faber. In principle, the findings could also help lead to therapies that stimulate formation of more collateral vessels in healthy people to reduce the severity of tissue injury in the event of a future arterial blockage, as well as in people who already have occlusions, thereby reducing damage and improving their recovery.

Earlier, Prof. Faber and colleagues began searching for the genetic factors responsible, focusing on collateral vessels in the brain, which are easier to image than in other tissues. By 2014, they narrowed the search to a small region on mouse chromosome 7, the variations of which accounted for nearly all of the differences in collateral development and tissue injury in the brains, hind limbs, and other tissues they examined.

In the new study, the researchers set out to identify the particular gene in this region that might explain the differences in collateral vessel development. From the 28 protein-coding genes in the region they narrowed down the focus to Rabep2, as they had previously found a Rabep2 variant in mouse strains with low collateral extent, whereas high-collateral strains had the normal Rabep2.

The variant differs from the normal gene in only a single nucleotide, at a location predicted to impair the function of the Rabep2 protein product. Using the new CRISPR gene-editing technology, the team tested the effect of this Rabep2 variant by replacing the normal gene in a high-collateral mouse strain, with the suspect defective variant gene. The result: the mice formed many fewer collaterals during development and had much greater stroke damage as adults. And this shift was even greater when the Rabep2 gene was deleted entirely.

Conversely, in mice from the low-collateral strain, replacing the defective variant gene with the normal gene induced the animals to develop the abundant collateral vasculature present in the high-collateral strain. These beneficially “edited” mice showed far more resistance to damage from stroke.

“We basically took mice of a strain that normally shows a very large area of tissue damage after an arterial obstruction in the brain, and – by editing that one gene – created mice that experienced much less damage after obstruction at the same site,” said Prof. Faber.

The team has now begun studies in patients with stroke to test for involvement of variants of Rabep2 and other related genes.

The study, by Lucitti JL et al, was published November 3, 2016, in the journal Stroke.

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