Sci. Aging Knowl. Environ., 20 April 2005
Harden My Heart
Gene spurs blood vessels to amass calcium deposits
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/16/nf29
It's a cruel irony of old age: Calcium leaks from bones, weakening them, yet accrues in blood vessels, hampering circulation. Researchers have now pinpointed a control circuit that prompts blood vessels to lay down calcium. Understanding the pathway could help researchers devise ways to dissolve the mineral buildup and maintain healthy blood flow.
In the elderly, diabetics, and the obese, blood vessels accumulate calcium deposits that resemble bone. These conglomerates stiffen arteries, hindering blood flow and encouraging the growth of fatty plaques. Previously, molecular biologist Dwight Towler of Washington University School of Medicine in St. Louis, Missouri, and colleagues found that mice genetically predisposed to obesity collect calcium in vessels when fed a high-fat diet. Furthermore, the rodents fire up a bone-building gene called Msx2 in their aortas. The researchers wanted to determine whether the gene's protein causes the calcium buildup.
They boosted Msx2 activity by infecting normal mice with a virus engineered to tote a copy of the gene. After 16 weeks on a high-fat diet, five of six manipulated animals amassed calcium in their arteries, whereas none of the uninfected mice did. Although cells in the vessels' outer layer carried extra Msx2 protein, calcium accrued in the middle of the vessel wall. Cells there produced excess alkaline phosphatase, an enzyme that stimulates calcium deposition. The team hypothesized that Msx2 sparks a bone-building signal in the outer cells that travels to the middle of the vessel.
To test the idea of a migrating bone-producing signal, the researchers studied mesenchymal cells, a type of stem cell that can turn into fat and bone; in addition, mesenchymal cells can become smooth muscle, one component of blood vessels. They engineered the cells to craft extra Msx2 and grew them in a culture dish. Then they collected the growth broth and added it to mesenchymal cells lacking bonus Msx2. The treatment enhanced signaling through the Wnt pathway, a protein network that turns precursor cells into bone cells and activates bonemaking genes. Moreover, it boosted alkaline phosphatase activity. Together, these observations suggest that the cells adopted a bonelike identity. In addition, mice with extra Msx2 produced more Wnt proteins in their aortas, and Wnt signaling increased compared with controls. The findings provide strong evidence that Msx2 and Wnt collaborate to incite calcification in arteries, says Towler. Next, he'd like to understand which cells lay down calcium. Smooth muscle cells in the middle of the vessel might revert to bonemakers, he says, or cells with stem cell properties might travel from the outer part of the vessel into the middle and morph into calcium depositors.
Vascular calcification is "something that has been ignored, but people are finally realizing that there is clinical significance to it," says bioengineer Cecilia Giachelli of the University of Washington, Seattle. The study "brings home the point that this process is highly regulated." Future efforts should try to clarify how aging, diabetes, or other diseases mobilize calcification, she says. Uncovering the mechanisms might reveal ways to stave off vessel calcification while preserving bone tissue. That potential should buoy hopes of repelling aging's double whammy.
April 20, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150