This week we profile a recent publication in Nature Neuroscience from the laboratory of Dr. Andy Shih at Seattle Children’s. Pictured are David A. Hartmann (below), Andrée-Anne Berthiaume (above, left), and Andy Y. Shih (above, right).
Can you provide a brief overview of your lab’s current research focus?
The research in our lab focuses on the smallest blood vessels that deliver oxygen and nutrients to the brain. In the human brain, an estimated 400 miles of blood vessels deliver blood to 100 billion neurons. This immensely complex task can easily go awry during human disease. We use an imaging approach called in vivo two-photon microscopy and mouse models to study how blood vessels grow, degrade, and respond to injury from birth to senescence. We hope that our research will yield new insight and approaches to improve cerebrovascular function in brain diseases that affect both children and adults.
What is the significance of the findings in this publication?
Of the 400 miles of blood vessels in our brain, the vast majority is composed of networks of minuscule capillaries where blood cells must squeeze through single file. The quality of blood flow through capillaries is important because they are a vast distribution network for blood. Not surprisingly, deficiencies in capillary flow and loss of capillary density lies at the root of many age-related brain diseases, such as Alzheimer’s disease.
A long-standing debate in the field has been whether blood flow through capillaries is actively regulated by cells surrounding the capillary wall. It is already well established that blood flow is regulated by arteries and arteriole of the brain, but studying capillaries in vivo has been technically challenging. This is because capillaries are difficult to resolve due to their small size. Further, their location downstream of arteries makes it difficult to discern autonomous control of blood flow at capillaries from influences from upstream arteries and arterioles.
In this study, we focused on pericytes, a cell type that covers the outside of capillaries. We show that pericytes exert local control of capillary diameter, but function on a slower time-scale than previously considered. To dissect the specific role of pericytes, we used advanced optical approaches to stimulate pericytes, or separately to ablate pericytes, in the living mouse brain. We found that stimulating pericytes led to constriction of capillaries and decrease in blood flow, while ablating pericytes led to aberrant dilation of capillaries and increased flow. This data provides firm evidence that pericytes indeed regulate blood flow autonomously in vivo, and are essential for optimal tuning of capillary tone and blood flow speed to properly extract oxygen and nutrients from the blood. The slow dynamics of pericytes suggest that this process is shaped over longer-term than the second-to-second fluctuations normally considered in cerebral blood flow dynamics.
What are the next steps for this research?
It will be important to understand the physiological conditions that lead to pericyte contractility and change in capillary tone. Our approaches provide proof-of-principle data that pericyte can and do regulate blood flow. However, the brain conditions and vascular signals that engaged pericyte tone in vivo remains poorly defined. Additionally, it is well known that capillaries become constricted in pathologies such as stroke, where pericytes aberrantly clamp down on capillaries and impede their flow. A key finding in our work is that pericyte contraction can be pharmacologically inhibited by a clinically-used drug call fasudil. This means that existing drugs may alleviate pathological vascular contractions both at the level of arteries (vasospasm) and capillaries.
This research was funded by:
This study was supported by grants to A. Shih from the NIH/NINDS (NS106138, NS097775) and NIH/NIA (AG063031, AG062738), the American Heart Association (14GRNT20480366), Alzheimer’s Association NIRG award (2016-NIRG-397149), and an Institutional Development Award (IDeA) from the NIGMS under grant number P20GM109040. The first author D. Hartmann was supported by awards NIH/NCATS (UL1 TR001450 and TL1 TR001451), and NIH/NINDS F30NS096868.
