In vivo systems for studying vascular development and arteriogenesis are inherently complex. In vivo, vascular cells involved in arteriogenesis and vascular remodeling experience many simultaneous stimuli that are difficult to control, including shear stress, stretch, oxygen levels, growth factors and substrate cues. In addition, in vivo systems are typically assessed in destructive ways - animals must often be sacrificed in order to gain a window onto arteriogeneic processes. Therefore, studying vascular development in vivo is time consuming, expensive, and subject to many factors that cannot be experimentally controlled. Conversely, standard cell culture systems are convenient, inexpensive and can be monitored nondestructively. However, simple 2-D cultures cannot replicate the complex shear stress and substrate environments that are present during in vivo arteriogenesis. For these reasons, we have developed novel culture systems that bridge the gap between these two existing methods. Our novel bioreactors allow the systematic control of cell type, substrate composition, soluble factors, and physical forces such as radial strain and shear stress. Hence, these bioreactors enable the control of many of the factors that are involved in vessel formation in vivo, but that cannot be controlled. In addition, these bioreactors simultaneously permit non-destructive observation of cellular behavior and developing vessels, thereby providing one of the key advantages of standard cell culture systems. These bioreactors provide powerful tools for enhancing our precise understanding of the mechanisms of arteriogenesis and vessel formation, and display many of the advantages of current in vitro and in vivo systems 9, 10. In this Bioreactor Core, we will utilize these two novel systems to address specific questions regarding the roles of shear stress and extracellular matrix composition on vessel development.
By providing 3-D bioreactors that are tunable, are fitted to impart mechanical stimuli, and can be used to non-invasively assess cell migration, tube formation, and branching, the resources in the Bioreactor Core are an innovative and essential aspect to this Program. The relevance to human health is that this Core will advance our understanding of vessel formation and repair in a range of cardiovascular disease processes.
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|Conway, Daniel E; Coon, Brian G; Budatha, Madhusudhan et al. (2017) VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol 27:2727|
|Dejana, Elisabetta; Hirschi, Karen K; Simons, Michael (2017) The molecular basis of endothelial cell plasticity. Nat Commun 8:14361|
|Conway, Daniel E; Coon, Brian G; Budatha, Madhusudhan et al. (2017) VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Curr Biol 27:2219-2225.e5|
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|Sawyer, Andrew J; Kyriakides, Themis R (2016) Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization. Adv Drug Deliv Rev 97:56-68|
|Kofler, Natalie; Simons, Michael (2016) The expanding role of neuropilin: regulation of transforming growth factor-? and platelet-derived growth factor signaling in the vasculature. Curr Opin Hematol 23:260-7|
|Baeyens, Nicolas; Larrivée, Bruno; Ola, Roxana et al. (2016) Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol 214:807-16|
|Kristofik, Nina; Calabro, Nicole E; Tian, Weiming et al. (2016) Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice. Blood 128:1642-50|
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