The brain is surrounded by layers of protective membranes, the innermost being infiltrated with a nourishing network of blood vessels, known as pial vessels. It has been assumed that during development, blood vessels in this pial network simply extend deeper into the brain to areas of increased metabolic need. Yet new findings reported by HMS researchers in the March 16 Nature Neuroscience have challenged this assumption, showing that vessels in the developing brain do not arise on demand from pial vessels but, instead, emerge in an autonomous manner based on an internal program.
The research team, led by Pradeep Bhide, HMS associate professor of neurology and director of neurology research at Massachusetts General Hospital, was initially interested in observing the anatomical and temporal relationship between blood vessel and brain cell growth. They started by looking at brain sections from mouse embryos at different stages of development and staining for blood vessels. Intriguingly, the team discovered that rather than developing in response to increased neuronal growth, blood vessel—or endothelial—cells actually emerged ahead of neurons and systematically migrated from the front to the back of the brain. Moreover, they displayed a unique structure—“like diamonds organized in a necklace,” said HMS instructor in neurology and first author Anju Vasudevan. “They were obviously regulated by something.”
A leading clue for what was regulating these endothelial cells came from the observation that their migration showed marked similarities to neuronal migration, which also extends from front to back, albeit a little later. Neuronal migration was known to be under the control of regulatory transcription factors. “So the first question that came to mind was, maybe the same transcription factors that regulate neuron migration regulate endothelial cell migration,” said Bhide.
Using a variety of tissue culture techniques and transgenic mice, the team subsequently demonstrated that not only did this necklacelike array of endothelial cells emerge and migrate independently but that it was, indeed, under the control of the same transcription factors that regulate neuron migration.
Bhide and his colleagues speculate that these endothelial cells are pioneers, traversing the brain in a regulated fashion, prior to other important events in brain development. The cells might even orchestrate these later events. “It opens up a lot of fundamental issues in neuroscience,” he said.
Knowing that endothelial cell growth is governed intrinsically could open up possibilities for genetic manipulation. Depending on the clinical condition, suppressing or improving vessel development could have applications for disorders of brain development, brain tumors, and conditions of interrupted blood flow such as stroke and ischemia. “This is like a key,” Vasudevan said. “There are now so many doors to open.”
