The major thrust of this proposal is to elucidate the role of blood rheology as a determinant of microvascular function in health and disease. Techniques of intravital microscopy will be applied to examine rheological factors which affect the resistance to blood flow in the anesthetized animal in terms of the biophysical behavior of erythrocytes and leukocytes in microvessels ranging in size from 100 Mu down to the true capillaries, 5-7 mu in diameter. Microvascular function will be examined in light of blood cell concentration and deformability, red cell aggregation, and leukocyte adhesion to the endothelium. To this end, hemodynamics will be studied in intestinal mesentery, omentum and cremaster muscle networks to derive quantitative indices of microvascular function in terms of: red cell velocity, pressure gradients, blood cell distribution and concentrations and hemoglobin oxygen saturation. Normal and abnormal blood rheology will be examined in individual microvessels, at branch points within a network and regionally throughout successive microvascular divisions. Studies are proposed to examine perfusion with: (1) normal blood cells, (2) during the in situ manipulation of blood cell properties by chemical reagents, e.g. dextrans to induce red cell aggregation or chemoattractants to elicit leukocyte to endothelium adhesion, and (3) following the introduction of blood cells with abnormal properties, such as by isovolemic exchange of red cells rigidified with glutaraldehyde, or a bolus infusion of abnormal leukocytes. In addition, from observations of microvessel diameter adjustments in response to the induced pathorheology, a delineation of compensatory vasomotor adjustments will be made to gain a clearer understanding of those rheological processes which affect tissue perfusion. In concert with these animal studies, parallel studies will be conducted to examine capillary blood flow in the skin (nailfold) of human subjects with hematological disorders. Mathematical modelling and computer simulations of microvascular blood flow will also be performed to gain an integrated view of the relationship between blood rheology and microvascular function. It is anticipated that the results of these studies will provide greater insight into the role of hemorheological determinants of microvascular function which will aid in the clinical management of a variety of pathophysiological states such as anemia, polycythemia, the low flow state, inflammation and blood cell disorders, to name a few.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research B Study Section (CVB)
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Pennsylvania State University
Biomed Engr/Col Engr/Engr Sta
University Park
United States
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Lipowsky, Herbert H; Bowers, Daniel T; Banik, Brittany L et al. (2018) Mesenchymal Stem Cell Deformability and Implications for Microvascular Sequestration. Ann Biomed Eng 46:640-654
Lipowsky, Herbert H; Lescanic, Anne (2017) Inhibition of inflammation induced shedding of the endothelial glycocalyx with low molecular weight heparin. Microvasc Res 112:72-78
Lipowsky, Herbert H; Lescanic, Anne; Sah, Rachna (2015) Role of matrix metalloproteases in the kinetics of leukocyte-endothelial adhesion in post-capillary venules. Biorheology 52:433-45
Lipowsky, Herbert H; Lescanic, Anne (2013) Shear-dependent adhesion of leukocytes and lectins to the endothelium and concurrent changes in thickness of the glycocalyx of post-capillary venules in the low-flow state. Microcirculation 20:149-57
Lipowsky, Herbert H (2013) In vivo studies of blood rheology in the microcirculation in an in vitro world: Past, present and future. Biorheology 50:3-16
Lipowsky, Herbert H; Lescanic, Anne (2013) The effect of doxycycline on shedding of the glycocalyx due to reactive oxygen species. Microvasc Res 90:80-5
Lipowsky, Herbert H (2012) The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases. Ann Biomed Eng 40:840-8
Lipowsky, Herbert H; Gao, Lujia; Lescanic, Ann (2011) Shedding of the endothelial glycocalyx in arterioles, capillaries, and venules and its effect on capillary hemodynamics during inflammation. Am J Physiol Heart Circ Physiol 301:H2235-45
Lipowsky, Herbert H; Sah, Rachna; Lescanic, Anne (2011) Relative roles of doxycycline and cation chelation in endothelial glycan shedding and adhesion of leukocytes. Am J Physiol Heart Circ Physiol 300:H415-22
Lipowsky, Herbert H (2011) Protease Activity and the Role of the Endothelial Glycocalyx in Inflammation. Drug Discov Today Dis Models 8:57-62

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