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Lung damage in babies with congenital heart disease under study

Trying to understand and stop the collateral lung damage that can occur in babies with congenital heart disease is the focus of a new study.

When a babys heart defect results in too much blood in the lungs, more blood vessels are made, apparently to handle the increased volume, then new blood vessel growth is abruptly halted.

You get this burst in the first month of life of blood vessel activity, then we think the system gets shut down and the lungs dont get any bigger, says Dr. Stephen M. Black, cell and molecular physiologist at the Medical College of Georgia Vascular Biology Center. What we are trying to work out is what are the mechanisms.

Dr. Black and his colleague, Dr. Jeffrey Fineman, a whole-animal physiologist and physician at the University of California, San Francisco, are using sheep whose four-chambered hearts are essentially identical to human hearts as a model to identify events that trigger blood vessel production, called angiogenesis, and the abrupt halt.

Their hope is the findings will lead to improved treatment for children born with heart defects.

The most common of the defects, ventricular septal defect, causes oxygen-rich blood that should be pumped out to the body by the left ventricle, to mix with oxygen-poor blood in the adjacent right ventricle. The blood then re-circulates to the lungs, resulting in too much volume in the lungs and too little in the body. The overworked heart, trying to take care of the body, can fail; the lungs, overwhelmed with blood, become congested.

Theres about three times as much blood flow going to the lungs as to the systemic circulation, says Dr. Black. Their heart rates go up to compensate. Over time, the heart muscle gets oversized from too much work.

And there is more going on. The blood volume in the lungs puts high pressure on blood vessels that, before birth, were idle because the mother provides the fetus with essentials such as oxygen and nutrients. There are shear forces from the blood coursing through vessels and stretch forces as they bulge to handle the load. Its a stimulus similar to constantly being born, says Dr. Black.

Dr. Black, who recently received a $1.2 million grant from the National Heart, Lung and Blood Institute, wants to know how these biomechanical forces alter growth factor expression and blood vessel growth in the lungs.

He believes many factors are involved, with transforming growth factor-beta 1, or TGF-1, and vascular endothelial growth factor, or VEGF, being critical. Hes found that TGF-1 increases VEGF, which increases blood vessel growth: within four weeks their animal model has two to three times the normal number of blood vessels. By eight weeks, the number is back to normal and the sheep typically dont survive much longer.

The process of how all this is regulated is complex and often conflicting. Endothelial and smooth muscle cells in blood vessels, pounded by biomechanical forces, switch on genes that enable them to get bigger. That includes producing more nitric oxide, a powerful vasodilator in the body.

Its a logical move: If your radius is twice as big, then the amount of shear is less, says Dr. Black. However, muscle cells dont like being distended, so they use growth factors to increase their numbers and squeeze back into shape, increasing shear force again. Now the body starts spitting out growth factors to grow more blood vessels to try to diminish shear force by creating more pipes for blood to flow through.

Nitric oxide helps drive this process as well by blocking TGF-1 inhibition so levels of that growth factor go up. In fact, just the act of stretching the vessels increases TGF-1 and ultimately VEGF expression. The plasminogen system, which activates wound-healing, also is a player, cleaving TGF-1 so it gets released. In turn, the increased TGF-1 activates a signaling pathway that activates a plasminogen activator inhibitor.

Endothelin, a powerful vasoconstrictor, is supposed to be decreased by shear force, but in the researchers animal model, its increased. Meanwhile, plenty of superoxides are produced that bind with nitric oxide and interfere with its effort to dilate blood vessels.

Other things are just weird. Endothelin typically works through the A receptor on the muscle cell and B receptor on the endothelial cell. In the animal model, endothelial cells have fewer of these receptors early on, and eventually, they switch to being expressed predominantly on muscle cells.

The idea is if we can understand what turns on angiogenesis, we might be able to regulate it a bit more, says Dr. Black. A major questions is, do all the extra blood vessels that initially result, apparently to help the body, do any good" The short answer is we dont know, says Dr. Black.

Hes seeking additional funding to look at the dysfunction in nitric oxide signaling that occurs. He thinks that is key to better regulating functional blood vessel growth.


Contact: Toni Baker
Medical College of Georgia

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