The vascularization of engineered tissues is critical to the ultimate success of tissue engineering as an organ replacement therapy. The formation of new capillary vessels from existing vasculature, or angiogenesis, also is linked to the pathogenesis of numerous diseases including cancer, and is regulated by local cues within the tissue microenvironment. The general goal of this renewal project is to understand the mechanism by which local extracellular matrix (ECM) properties regulate endothelial cell invasion and sprout morphogenesis required in angiogenesis, and to use these insights to guide design of biomaterials to enhance angiogenesis for clinically relevant applications. The investigator has found that adhesion to ECM generates not only biochemical, but also mechanical signals that are important in driving endothelial cell function. Preliminary studies from the investigator suggest that ECM stiffness, adhesiveness, and degradability could be used to regulate the angiogenic invasion process through such materials by modulating key signaling pathways regulating the actin cytoskeleton. In this proposal, the investigator proposes to further investigate the role of these ECM cues in regulating angiogenic behaviors. The project proposes to develop biomaterials to investigate the contributions of different matrix properties and their cooperation in regulating angiogenesis using both in vitro and in vivo models, and to examine the morphodynamics of developing vasculature within those materials. The investigator will examine whether these materials can be used to control the architecture of angiogenic vessels. Together, these studies will define the mechanisms by which local structural and mechanical properties within ECM modulate endothelial cell function and capillary morphogenesis, and establish new biomaterials design strategies to promote angiogenesis in ex-vivo engineered tissues as well as native ischemic tissues.
The formation of new capillary vessels in vivo, or angiogenesis, is a rate limiting challenge in the development of engineered implants for organ replacement. Angiogenesis is also critical to many disease processes, including tumor growth and recovery from ischemia. This project is designed to develop a better understanding of how angiogenesis is regulated by local adhesive and mechanical cues, such that we may better design biomaterials to control the growth of blood vessels in tissues.
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