RHEOLOGICAL DETERMINANTS OF MICROVASCULAR FUNCTION

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DESCRIPTION (provided by applicant): The overall goal of this research is to elucidate the role of blood rheology as a determinant of microvascular function in health and disease. To this end, techniques of intravital microscopy will be applied to evaluate the extent to which blood cell properties affect the resistance to blood flow in vessels ranging from the true capillaries, to the arterioles and venules which serve them. The general aim of the proposed studies is to elucidate the role that hemodynamic shear stresses play in affecting the structure of the endothelial cell glycocalyx during models of ischemia followed by reperfusion, and during inflammation. During the prior period, this research has suggested that the composition of the endothelial glycocalyx may change in response to inflammatory mediators and during ischemia/reperfusion. Glycan components have been shown to be shed in response to G-protein mediated signaling resulting from modulation of shear stresses and stimulation by the peptide fMLP. To further elucidate the shear dependency of these phenomena, 4 specific aims are now proposed. In aim #1 the composition of the glycocalyx will be explored in venules by intravital fluorescence microscopy using lectins specific for galactose and glucose residues, antibodies for heparan and chondroitin sulfate, and hyaluronan binding protein. In aim #2, the shear stress dependency of venule glycan content will be explored during graded reductions in flow and duration of ischemia, and compared to reductions in shear stress incurred by reducing blood viscosity using hemodilution. In aim #3, the relative amounts of glycan accumulation and shedding during ischemia/reperfusion and with fMLP stimulation will be determined throughout the hierarchy of arterioles, capillaries and venules. In aim #4, the effect of glycan accumulation and shedding on the resistance to flow in the true capillaries will be determined. The results of these studies will provide insight into the role of hemodynamic interactions with the microvessel wall and aid development of therapeutic strategies to treat ischemia and inflammation.