The researchers also found that a substance produced by the body known as vascular endothelial growth factor (VEGF) causes the immature cells to form new blood vessels at a faster rate. The findings are published in the Sept. 3 issue of the Proceedings of the National Academy of Sciences.
"This finding has important implications for tumor biology, gene therapy and the treatment of various congenital disorders," says principal investigator Mark S. Sands, Ph.D., associate professor of medicine and of genetics and a member of the hematopoietic development and malignancy research program at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
Generally, scientists have believed that the cells, known as endothelial progenitor cells (EPCs), contribute to new blood-vessel growth only before birth. The round EPCs mature into the flat, spindly endothelial cells that form capillaries and line blood vessels. In later life, EPCs also are known to help build the uterine wall during ovulation and to help repair damaged vessels during wound healing and recovery from ischemia. They also contribute to tumor growth.
In neonates, however, new blood vessels are thought to grow only from pre-existing endothelial cells. "This is the first demonstration that EPCs contribute to the development of new blood vessels during normal tissue growth following birth," says Pompee P. Young, M.D., Ph.D., clinical fellow in transfusion medicine and lead author of the study.
Young hypothesized that early neonates develop new blood vessels so rapidly that EPCs may be needed to keep pace with the demand. Earlier research by others also indicated that levels of VEGF, which attracts and stimulates the growth of EPCs, are higher in neonates, which also suggests that EPCs contribute to the development of blood vessels in newborns.
Young, Sands and doctoral student A. Alex Hofling tested the idea using bone marrow cells isolated from adult mice. The investigators injected the cells, which contained a chemical marker to identify them, into newborn mice within three days of birth. Some of the animals also were injected with VEGF. A few mice were injected at four weeks of age to test whether EPCs contributed to blood-vessel growth in older animals.
The mice were examined two, four and eight weeks after receiving the bone marrow cells. In the newborn mice, researchers found high numbers of donor EPCs incorporated into new blood vessels in all the tissues examined, though for technical reasons the researchers looked most closely at the heart and liver. Evidence of EPC uptake declined sharply after eight weeks, and the investigators found no evidence that EPCs contributed to new blood-vessel growth in mice that received cells at four weeks of age.
"This suggests that bone-marrow-derived EPCs contribute to new blood-vessel formation in the newborn period," says Young.
The researchers also found that high-dose VEGF increased the density of blood vessels in the heart by more than five times after two weeks, and almost eight times after eight weeks compared to animals that received marrow cells and no VEGF. They found a smaller but significant increase in the liver.
"Overall, the study suggests that there may be a window during which VEGF regulates the development of new blood vessels," says Sands.
The study has important implications for pediatric medicine, says the paper's editor, M. Judah Folkman, M.D., Julia Dyckman Andrus Professor of Pediatric Surgery at Boston Children's Hospital and Harvard Medical School and a specialist in blood vessel development.
For example, some infants develop benign tumors of the blood vessels known as hemangiomas that can be very dangerous says Folkman. "This study suggests that endothelial cells may be trafficking into those tumors, enabling them to grow. Perhaps by measuring the number of endothelial progenitor cells in the blood we can predict which babies have dangerous tumors and should be treated by drugs and which babies have tumors that will regress early and don't require drug treatment."
The study also may help explain why EPCs travel from the bone marrow to malignant tumors, as other research has recently shown, says Folkman. "If a tumor makes high amounts of VEGF, as some do, it would make it easier for endothelial cells to settle in that tumor and form new blood vessels."
Young PP, Hofling AA, Sands MS. VEGF increases engraftment of bone marrow-derived endothelial progenitro cells (EPCs) into vasculature of newborn murine recipients. Proceedings of the National Academy of Sciences, 99(18), 11951-11956, Sept. 3, 2002.
Funding from National Institute of Diabetes and Digestive and Kidney Diseases and from the National Heart, Lung and Blood Institute supported this research.