To sustain the health of tissues in the body, the circulatory system needs to efficiently and continuously supply oxygen and nutrients to every living cell within the tissue. Capillaries, the site of gas exchange between circulating red blood cells and the surrounding tissue, constitute a majority of the vasculature. Yet, how red blood cells navigate the thousands of miles of branching capillaries to specifically deliver their cargo to the cells in need remains unknown. It has generally been thought that blood flow though capillaries is mostly passive flow. My research demonstrates that capillary blood flow is finely regulated, and flow is directed at capillary junctions by contractile pericytes. My current focus is understanding the cellular and molecular mechanisms regulating blood flow entering the capillary microcirculation. Specifically, I am working to define the role of contractile pericytes in the dynamic distribution of red blood cells within capillary networks of the brain.
Pericyte Calcium Dynamics
The goal is to characterize the ion channels and molecular mechanisms contributing to pericyte calcium dynamics and contraction. In particular, elucidating the possible role of Transient Receptor Channels (TRP) in pericyte function.
Comparing calcium dynamics and contractions of a group of vascular smooth muscle cells (left) and individual projections of a single pericyte (right).
Junctional Control of Capillary Blood Flow
We are testing the hypothesis that pericytes play an important role in structurally and dynamically regulating the morphology of capillary junctions to insure the proper distribution of red blood cells throughout the capillary network.
In vivo calcium imaging of junctional pericyte demonstrating one-sided (arrowhead) and sphincter-like (open arrowhead) changes in vessel diameters.
Pericytes and Alzheimer's Disease
We are examining the effects of amyloid-β on perciyte calcium dynamics, pericyte function, and capillary blood flow. Eventually, the progressive loss of pericyte function at capillary junctions leads to inefficient perfusion of the capillary network, affecting the health and function of neurons.
Image of Methoxy-X04 staining of amyloid-β plagues (yellow) in cerebral vasculature of 12-month old 5xFAD transgenic mice with TRITC (red)-dextran illuminating the vasculature. Scale Bars: 50 µm.
Optogenetic Manipulation of Capillary Blood Flow
Using transgenic mice expressing optogenetic actuators, we examined the intra- and intercellular propagation of electrical and chemical signals between projections of a single capillary pericyte and between capillary pericytes and upstream arterioles.
Light-evoked generation of DAG/IP3 in one capillary pericyte had no affect on the contractile state of the adjacent pericyte.
Intercellular Calcium Signaling Between Pericytes and Endothelial Cells.
To examine the local calcium signaling circuitry between contractile pericytes and the underlying capillary endothelial cells, we use mice expressing endothelial cell-specific green calcium biosensor and a smooth muscle/pericyte-specific red calcium biosensor.