About the Lab
At present we have two major areas of investigation, with several projects underway in each.
During inflammation, different populations of white blood cells emigrate from the vasculature into the tissue: also during inflammation, fluid and proteins leave the vasculature, causing edema in the surrounding tissue. We recently made the discovery that the adhesion molecule ICAM-1, which is mediates neutrophil adhesion to the endothelium, also initiates signals that regulate the permeability of the wall to albumin. Albumin is a molecule that is critical in maintaining fluid balance and is also a critical carrier of hormones and other essential proteins. We discovered that different signaling pathways are turned on in normal versus inflamed endothelium; now we need to find out whether these signals regulate different pathways through the endothelial barrier, and their characteristics. Where leukocytes interact within the vasculature is determined by adhesion molecule expression on the vessel wall, by the local fluid dynamics, and by the morphology of the vasculature. Leukocytes roll, adhere, crawl along the lumen and then emigrate (mostly, although not always) through junctions between endothelial cells. We want to know why these events happen in some areas of the microcirculation and not others, and what the different mechanisms are. We combine quantitation of leukocyte behavior with calcium signaling measurements, measurements of adhesion- and junctional-protein densities, and analysis of the local fluid microenvironment.
When skeletal muscle contracts, metabolites are released that cause vasodilation in nearby arterioles, thus matching blood flow to demand. Mechanisms underlying this very local response are unresolved, and, importantly, how it is spread along the vessel wall so as to enable a co-ordinated increase in blood flow is not known. Gap junctions are important in many communicated responses, but we showed that the metabolic response is propaged differently. We have published work showing that endothelial calcium changes are essential, and we have also shown that purines (such as adenosine) that are released when muscles contract, initiate propagated responses. We are trying to find out which receptors, and which endothelial signaling mechanisms, are critical for this response.
We recently showed, in an important new paper, that the extracellular matrix proteins that surround arterioles respond to the mechanical events associated with muscle contraction with signals that cause vasodilation. The ECM protein fibronectin is key in this newly identified mechanosignaling pathway. We are collaborating with the Hocking lab to explore the mechanisms underlying the response. Because ECM proteins change as people age, and because it is well known that the vasculature becomes less responsive in older adults, this finding is likely to be very important in planning therapeutic interventions as our population ages.