"It really looks like angiogenesis and adipogenesis are joined at the hip," says Rakesh K. Jain, PhD, director of the Steele Laboratory for Tumor Biology at MGH, senior author of the study, "These new findings are helping us understand just how closely these processes work together and identify new ways of controlling these functions to meet important medical challenges."
Previous research had suggested connections between these two processes. A 2002 study from the laboratory of angiogenesis pioneer Judah Folkman, MD, at Children's Hospital Boston found that when anti-angiogenesis agents were given to mice genetically programmed to develop obesity, the mice did not gain weight. The current MGH study reveals the mechanism behind this interaction.
Led by three investigators from the Steele Laboratory at MGH – Dai Fukumura, MD, PhD, Akira Ushiyama, PhD, and Dan Duda, DMD, PhD – the research team began examining the process by which fat-cell precursors called preadipocytes differentiate into mature adipocytes (fat cells). They first implanted normal preadipocytes into chambers beneath the skin of immune-deficient mice, and as expected the cells differentiated into mature fat cells. But not only did blood vessels develop to supply the growing tissue, they also formed efficient, organized networks, something that rarely happens outside of natural growth conditions.
"We've been trying to grow organized, mature blood vessel networks for more than 25 years," says Jain, "and this is the first time I've seen that happen under experimental conditions."
To block fat-cell differentiation, the researchers implanted mice with preadipocytes that had an inactivated form of a protein required for fat cells to mature. Not only did the implants neither grow nor differentiate into mature fat cells, but there also was virtually no blood vessel development. Similarly, introduction of an antibody against a protein key to angiogenesis both prevented blood vessel development in the implants and also kept the fat cell precursors from maturing.
"These processes now appear to be coupled at very fundamental levels," Jain says. "And we are starting to identify the proteins involved and the stages at which they are active." Jain is the A. Werk Cook Professor of Radiation Oncology at Harvard Medical School.
Better understanding of the interaction between angiogenesis and adipogenesis and the development of ways to control and direct the processes could have a wide range of medical applications. Anti-angiogenesis compounds are already being evaluated as cancer-fighters, and the current results suggest they may be useful in combating obesity as well. The observation that blood vessels growing in response to adipogenesis form organized networks – in contrast to the inefficient networks that develop in and around tumors – might help with efforts to grow new organs and tissues, since the development of a circulatory system is a key challenge in the field of tissue engineering.
Fukumura, Duda and Ushiyama – who is now with the National Institute of Public Health in Tokyo – are co-first authors of the Circulation Research paper; other co-authors are Lei Xu, MD, PhD, Joshua Tam, BS, and Igor Garkavtsev, MD, PhD, of the Steele Lab at MGH, and Krishna Chatterjee, PhD, of the University of Cambridge, England. The study was supported by grants from the National Institutes of Health.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.