The general goal of this renewal proposal continues to be to understand the biomechanical mechanism by which extracellular matrix (ECM) regulates capillary development. During the last grant period,we used microfabricated substrates containing ECM-coated adhesive islands of defined size and shape on the micronscale to demonstrate that ECM governs whether capillary endothelial(CE) cells will grow, differentiate, undergo apoptosisor migratein response to angiogenic factors based on its ability to resist cell tractional forces, alter tension in the cytoskeleton (CSK), and thereby modulate cell shape. CSK tensionwas found to be dependent on mechanical interactions between contractile microfilaments, microtubules, and ECM adhesions and to require efficient mechanical coupling between integrin receptors and the CSK through binding of focal adhesion proteins,such as vinculin. Maintenance of this physical linkage also was found to be required for formation of lamellipodia stimulated by the small G protein, rac, where as pharmacological inhibition of CSK tension generation rapidly suppressed lamellipodial movement. Thus, the main objective of the present proposal is to extend our ongoing studies and to focus on the biomechanical mechanism bywhich ECM: regulates direction almigration and vascular patterning in response to angiogenic stimuli.
The specificaims i nclude: 1) to explore how changes in ECM structure and mechanicsalter CSK tensionand focal; adhesion formation,2) to determine how mechanical interactions between CE cellsand ECM control amellipodia extension and directional migration, and 3) to explore whether local changes in CSK tension contribute to pattern formation during capillary morphogenesis.
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