June 14, 2010

New Mechanism for Clearing Blocked Microvessels

Three-part image of blood vessel showing a blockage that is encapsulated and then expelled through the outer blood vessel wall Time-lapse images of a blockage in a mouse brain blood vessel becoming encapsulated and expelled through the outer blood vessel wall. On Day 1, the membrane of the blood vessel starts to extend around the orange cholesterol blockage (arrow). By Day 3, the membrane has surrounded the cholesterol and created a pathway to the outside of the blood vessel (arrowhead). On Day 5, the blockage has moved oC.K. Lam, et al., Nature.

Researchers have identified a previously unknown process by which the smallest blood vessels remove blood clots and other blockages in mouse brains. The finding provides insight into a mechanism that may be involved in recovery from stroke as well as age-related cognitive decline, Alzheimer’s disease and other brain conditions.

The brain needs uninterrupted blood flow in order to function properly. Persistent blockage of blood vessels in the brain can reduce or stop blood flow, limiting the supply of oxygen and nutrients to brain cells. This can lead to impaired communications between nerve cells and ultimately cell death.

The body has developed various mechanisms to maintain the brain's blood supply. Blockages can often be cleared by processes that either disintegrate or wash them out. But not all blockages in the smallest blood vessels of the brain, known as microvessels, can be completely cleared by these mechanisms.

Dr. Jaime Grutzendler and colleagues at the Northwestern University Feinberg School of Medicine set out to explore whether or how blood flow blockages can be cleared in microvessels. They turned to a newly developed technique, called 2-photon imaging, that allowed them to view microvessels in the brains of living mice. Their work was supported by NIH's National Institute on Aging (NIA) and the Howard Hughes Medical Institute.

In the May 27, 2010, issue of Nature, the scientists reported discovering a new mechanism by which blockages in brain microvessels can be cleared. Within 2 to 7 days after a blockage, the cells lining the blood vessel wall engulf the remaining portion of a blockage. The cells encapsulate the blockage, sealing it off from the interior of the blood vessel. Then the blocking material is expelled outside of the vessel, restoring blood flow to the affected area.

The researchers showed that this complex new protective mechanism involves the activity of an enzyme called matrix metalloprotease 2/9, which is known to play a role in blood vessel development. MMP-2/9 inhibitors delayed removal of blockages in the mice. These inhibitors have previously been shown to worsen recovery after stroke.

The researchers also found that the ability to move a blockage out of a microvessel diminishes with age. Young mice (4 months) were able to clear blockages more quickly and thoroughly than older mice (22 months). The incomplete removal of blockages in the brains of older mice led to a persistent shortage of oxygen to the surrounding nerve cells, damage to the connections between nerve cells and nerve cell death.

"These are intriguing findings," says NIA Director Dr. Richard J. Hodes. "They open new avenues of basic research that may increase our understanding of how microvessels are maintained in the brain and throughout the body."

"The reduced efficiency of this protective mechanism in the older brain and its effect on the function of nerve cells in the brain may significantly contribute to age-related cognitive decline," says Dr. Suzana Petanceska of NIA. "This may also be part of the mechanism by which vascular risk factors such as high blood pressure and diabetes increase the risk of Alzheimer's disease with age."

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