Brain’s blood supply guides its own development

MGH-led study finds vascular development guided by intrinsic factors, not neuronal needs

BOSTON - March 2008 - A new study from investigators at Massachusetts General Hospital (MGH) paints a radically different picture of how the brain’s blood supply develops. Their report in the journal Nature Neuroscience, which has received early online release, describes how blood vessels in the brain grow according to their own agenda beginning early in fetal life and finds that the vasculature of embryonic brain may actually guide later development of brain cells and their connections.

“Until now it was believed that, as our brains grew and as neuronal connections and nerve fibers formed, blood vessels carrying oxygen and other nutrients grew passively to meet the brain’s metabolic needs,” says Pradeep Bhide, PhD, director of Research for MGH Neurology and senior author of the paper. “This new study calls for a complete revision of that model of brain vascular development and places emphasis on genetic mechanisms guiding the proliferation and migration of the cells that make up blood vessels.”

It is common knowledge that the brain receives the lion’s share of the blood supply and that even brief interruption of cerebral bloodflow can result in stroke and permanent brain damage. The anatomy of the brain’s vascular networks is as complex and fascinating as neuronal networks, but surprisingly little has been known about how the lifelong close relationship between blood vessels and brain cells develops.

To investigate this question, the MGH scientists and their collaborators labeled endothelial cells, building blocks of blood vessels, with fluorescent markers and followed their complex behaviors and migrations as they maneuvered to build tiny new blood vessels in fetal brains of mice. They found that the cells divided and migrated and new blood vessel assembly occurred in a highly coordinated and orderly fashion. Transgenic mouse models confirmed that the endothelial cells were responding to their own genetic programs - not those governing the formation of neurons - and not merely reacting to the growing metabolic demands of brain tissue.

“In addition, we found that some of the genes that regulate neuronal development also regulate endothelial cell development, which unifies the principles of development of both cell types. Our study also finds that endothelial cells in the fetal brain may guide development of neuronal networks and places the embryonic brain’s vasculature in a position to play dual and independent roles of supplying nutrition and carrying instructive signals for brain development,” says Bhide, who is also director of the MGH Neuroscience Center and an associate professor of Neurology at Harvard Medical School. He and his colleagues anticipate that insights emerging from this study could improve understanding of brain malformations and developmental disorders by shifting focus towards mechanisms regulating development of blood vessels in the fetal brain.

Anju Vasudevan, PhD, of the MGH Neuroscience Center is the lead author of the Nature Neuroscience article. Study co-authors are Jason Long, PhD, and John Rubenstein, MD, PhD, University of California at San Francisco; and James Crandall, PhD, University of Massachusetts Medical School. 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 $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.