Hemodynamic Forces in Vascular Remodeling

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DESCRIPTION (provided by applicant): In this proposal we address the hypothesis that hemodynamic forces, such as wall shear-stress, are central to normal vascular formation and remodeling in mouse embryonic development. The proposal that shear stress plays an important role has been made many different times and there has been some support for this theory; however, few quantitative experiments have tested it in vivo in an intact embryo. To this end, the proposed work will develop image-based quantitative indices of morphological remodeling which allow statistical comparison with measured hemodynamic properties in vivo. The proposal requires technical development of the non-invasive imaging techniques, particularly magnetic resonance microscopy (MRM) imaging. MRM will be used to measure blood plasma velocity, blood volume and regional flow across the whole embryo using endogenous image contrast alone. Confocal laser scanning microscopy (CLSM) will address direct time-of-flight measurements of erythrocyte flow and endothelial motion over more limited regions of the forming embryonic vasculature. Use of two imaging modalities allows complementary flow quantitation and cross-validation. Experimental perturbations of flow, pulsatility and hematocrit result in changes in hemodynamic forces on the developing vasculature. Perturbations will be characterized with both MRM and CLSM; the changes in hemodynamic forces will be correlated with morphological remodeling indices. Overall, these approaches will define the dynamic changes in morphology that occur in normal development and when blood flow is disrupted. Morphological changes will be related to quantitative data revealing how flow and development are interlinked. These experiments will establish a model system to study fluid effects on vascularization. Once this model has been established, studies to understand the interplay between mechano-sensory signals and genetic signaling pathways can begin. (End of Abstract)