BOSTON--Cicero, King James II of Scotland, and Mikhail Gorbachev may have differed greatly as politicians, but they do have one thing in common: They all had, or have, a prominent vascular birthmark. That alone, of course, does not distinguish these leaders from common folk: One out of every three children has one. These "mother's marks" include everything from the harmless "storkbite" on the neck of newborns, to "port-wine stains," blemishing the three statesmen, to crippling, invasive growths of aberrant blood vessels.
Historical belief notwithstanding--namely that such marks occur when passionate longings of the pregnant mother imprint themselves on her fetus--Bjorn Olsen and his collaborators are now offering a more modern explanation for their cause. In the December 27 Cell, researchers led by Olsen, Hersey Professor of Cell Biology at Harvard Medical School, report their discovery of a genetic mutation responsible for venous malformations, the most common type of birthmark. In addition, the researchers describe what role the gene might play in the assembly of veins during embryogenesis, and how its faulty version might lead to malformations.
Together with two related papers in the same issue of Cell, this work signifies "exciting progress in vascular biology, because [it] begins to reveal the molecular basis of vascular remodeling," writes Judah Folkman, professor of anatomy and cell biology at Children's Hospital, Boston, in an accompanying review in Cell.
The study foreshadows a coming wave of organogenesis research. In this new area of investigation, scientists are reversing the century-old reductionism in biology. After years of going from organism to organ to cell to DNA, researchers are now taking their molecular knowledge back to higher levels of organization. Specifically, they are trying to decode the molecular signals that different cell types exchange as they gradually arrange themselves into the complex structures that are our organs.
Three years ago, researchers in Olsen's group and that of John Mulliken, associate professor of surgery at Children's Hospital and a leading authority on vascular birthmarks, started analyzing the genes of a family whose members suffered from venous malformations. Midway through their study, a patient with similar symptoms sought Mulliken's help. It turned out that this person belonged to another branch of the same family, and that the two branches were completely unaware of each other's existence. Armed with data from this large clan and another, unrelated family, the researchers were able to pinpoint the gene. It codes for TIE-2, a receptor lodged in the cell membrane of endothelial cells, which line the inside of blood vessels.
But how could TIE-2 lead to birthmarks? The likely answer reveals as much about how normal veins form as about their malformations.
The assembly of veins occurs as a series of distinct steps. First endothelial cells form tubes and sprout branches. Then precursors of smooth muscle cells migrate towards the tubes, and upon physically touching the tubes receive a signal that prompts them to differentiate and wrap themselves tightly around the tube to build the vessel's wall.
This process is coordinated by an extensive molecular dialog between the endothelial cell tubes and their environment, says Olsen. Although the exact function of TIE-2 is still mysterious, the researchers found that in the affected families, a tiny mutation sends the corresponding protein into overdrive, allowing it to break free of its normal molecular controls.
He suspects that as part of the normal molecular dialog, TIE-2 is activated and controlled by a protein binding to it--a ligand-- that is secreted by cells in the environment of the tubes. Next, TIE-2 induces the endothelial cell to secrete a yet unknown signal, which diffuses into the vicinity and primes the smooth muscle cell precursors to prepare for migration towards the tubes. He also proposes that TIE-2 is part of a feed-back loop between the endothelial cells and the smooth muscle cells that ensures that when new tubes sprout, their walls are built as well. In patients with venous malformations, this communication is jammed, so that new tubes keep sprouting but never receive proper walls. In severe cases these incomplete veins meander wildly, forming huge, abnormal tissue bulges.
Though this scenario is speculative, Olsen says, the two coincident papers support it by fleshing out the still-sketchy picture. The first study, led by researchers at Regeneron Inc., announces the discovery of the ligand for TIE-2, a new factor called angiopoietin-1. It confirms Olsen's hunch that angiopoietin-1 is made by cells in the tubes' vicinity. The second paper, co-authored by Thomas Sato, assistant professor of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School knocked out the angiopoietin-1 gene in mice. Intriguingly, these mice had defects in their blood vessels that mirror those of veins in human birthmarks.
This research illustrates how the study of human conditions can advance basic understanding of blood vessel formation--a prerequisite for the development of effective therapies for all diseases in which this process goes awry, most notably cancer. Even though it may take another 10 years until enough is known to devise drugs that treat the root cause of birthmarks, "there is nothing impossible about it; we can do it," says Olsen.
This research was partly funded by the National Institutes of Health.
Additional authors of the Cell article are Mikka Vikkula, Laurence Boon, Matthew Warman, Kermit Carraway III, John Diamonti, Lewis Cantley, all at Harvard Medical School, Boyan Goumnerov and John Mulliken at Boston's Children's Hospital, Jennifer Calvert at Duke University Medical Center, and Krystyna Pasyk at the Universtiy of Michigan.
Editors, please note: Bjorn Olsen can be reached through Bill Schaller or Don Gibbons.