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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107205-03
Application #
8607988
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Kofler, Natalie; Corti, Federico; Rivera-Molina, Felix et al. (2018) The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. J Biol Chem 293:4805-4817
Chen, Dongying; Simons, Michael (2018) Reprogramming the Endocardium: Trials and Tribulations. Circ Res 122:913-915
MacLauchlan, Susan C; Calabro, Nicole E; Huang, Yan et al. (2018) HIF-1? represses the expression of the angiogenesis inhibitor thrombospondin-2. Matrix Biol 65:45-58
Zhang, Feng; Zarkada, Georgia; Han, Jinah et al. (2018) Lacteal junction zippering protects against diet-induced obesity. Science 361:599-603
Yu, Pengchun; Wu, Guosheng; Lee, Heon-Woo et al. (2018) Endothelial Metabolic Control of Lymphangiogenesis. Bioessays 40:e1700245
Bellini, C; Kristofik, N J; Bersi, M R et al. (2017) A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. J Mech Behav Biomed Mater 71:397-406
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 27:2727
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
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

Showing the most recent 10 out of 54 publications