With only a single hormone as her guide, Kathleen Caron, Ph.D., a recipient of a 2001 Burroughs Wellcome Fund Career Award in the Biomedical Sciences, has toured nearly every human system. The hormone, adrenomedullin, is a powerful blood-vessel dilator that is present in cells throughout the body, playing a role in such diverse activities as metabolism, heart function, thirst, and stress.
For her part, Dr. Caron has shown that adrenomedullin is necessary to successful pregnancies. Blood levels of the hormone are four to five times higher than normal by the third trimester, returning to prepregnancy values within 48 hours after delivery. But this dramatic increase often doesn’t happen in women who experience pregnancy complications, Dr. Caron said.
Dr. Caron thinks that adrenomedullin is critical for establishing blood flow to the embryo. Both mother and embryo increase their levels of the hormone at the site in the uterus where the embryo becomes implanted. And in a healthy pregnancy, the placenta, which links mother and fetus, secretes increasing amounts of the hormone as pregnancy progresses.
Dr. Caron said the discovery that pregnancy difficulties are sometimes linked to lower than normal adrenomedullin levels may offer an explanation for complications such as preeclampsia, miscarriage, and gestational diabetes.
An assistant professor of cell and molecular physiology and genetics at the University of North Carolina-Chapel Hill, Dr. Caron first noticed the connection between the hormone and fertility during her postdoctoral fellowship at UNC.
Working with Nobel laureate Oliver Smithies, D.Phil., Dr. Caron was learning how to produce genetically altered mice. “I was hooked on the idea of modeling human disease in mice,” she said. “I really wanted to learn how to do it myself.”
About a year into the postdoc, Dr. Smithies told Dr. Caron she looked bored. He was right, she now recalls. Dr. Smithies gave her a blank check to develop her own project, with one condition: she had to make a mouse with high blood pressure.
Dr. Caron searched the medical literature for a gene that, if missing, might make mice hypertensive. She picked adrenomedullin, a recently discovered peptide, and developed a “knockout” mouse missing the gene. For a model of high blood pressure, the choice was a failure. “They were not hypertensive,” Dr. Caron said. “Its major function is not to regulate blood pressure.”
But when the knockout mice gave birth to malformed litters, Dr. Caron realized she was on the trail of something new.
Female mice with a genetic mutation that reduces adrenomedullin levels by 50 percent have poor fertility and small litters. Dr. Caron found that their embryos implanted abnormally in the uterus and were spaced too closely together, leading to poor fetal growth. The father’s hormone levels, on the other hand, did not have the same effect.
“The clinical implications are that women who have mutations in the gene responsible for expressing adrenomedullin might have greater susceptibility to pregnancy problems,” Dr. Caron said.
Adrenomedullin’s influence is even more apparent in mice—both males and female—that are missing both copies of the gene and so cannot produce any hormone. These animals die before birth because of massive edema—swelling from too much fluid. They also have unusual heart defects.
This finding, Dr. Caron said, may offer hope to the 100 million people worldwide who suffer from lymphedema. This debilitating condition occurs when the lymphatic system, which transports fluid throughout the body, fails to work properly, leading to extreme swelling. In the United States, lymphedema is a common complication of cancer treatment, while in tropical regions a parasitic infection is most often responsible for the condition.
Dr. Caron and her students recently showed that mouse embryos that lack sufficient adrenomedullin fail to develop a normal lymphatic system. The researchers found that such animals, not only are missing some of the myriad of vessels comprising the lymph system, but the main routes in the system, the jugular vessels, are smaller and have lower capacity. These problems cause fluid backup and swelling, not unlike the commuter traffic on a poorly planned freeway system.
Further experiments in cell cultures have revealed that adrenomedullin drives the growth of lymphatic endothelial cells, which form the walls of lymph vessels.
The results suggest that adrenomedullin may prove to be an effective drug target for treating lymphedema, Dr. Caron said. Conversely, blocking the hormone potentially could prevent the spread of cancer, she said, because lymph vessels that grow in tumors provide an on-ramp to the lymph system, allowing cancerous cells to spread throughout the body.
Dr. Caron plans to continue investigating the role of adrenomedullin in humans through mouse models and cell biology. “What I go back to is the clinical data and ask, What do physicians think this is doing in humans? If I don’t see an immediate link to human disease, I’m less inclined to do it,” she said.
Among current projects, Dr. Caron is investigating the signaling pathways that communicate adrenomedullin’s instructions to cells. These pathways are activated by proteins called G-protein coupled receptors. As more than 70 percent of pharmaceutical drugs act on G-protein coupled receptors, understanding adrenomedullin and its receptors is a promising path to new treatments for human disease, according to Dr. Caron.
Drilling down from the mouse to the cell is both a new avenue of research and familiar ground for Dr. Caron.
After earning undergraduate degrees in biology and philosophy at Emory University in Atlanta, she completed her graduate degree at Duke University, in Durham, N.C., where her father, Marc Caron, Ph.D., is a professor of cell biology. The elder Dr. Caron, a leader in G-protein coupled receptor signaling, passed his love of biology to his daughter.
“I grew up in the lab,” she said. By age 16, she was devoting her summers to working in numerous laboratories at Duke, gaining experience in a diversity of fields such as classical biochemistry and pediatric brain tumors. But she never intended to follow in her father’s footsteps.
“I always wanted to do research, but the one thing I swore I wouldn’t do is G-protein coupled receptor signaling,” she said. “Fate can be funny sometimes.”
By Becky Oskin, a freelance science writer is currently based out of Chapel Hill, N.C. We wish her luck on her upcoming move to California.