Effects of biomechanical and biochemical stimuli on angio- and vasculogenesis in a complex microvasculature-on-chip
Dario Ferrari,
Arunima Sengupta,
Lyong Heo,
Laszlo Pethö,
Johann Michler,
Thomas Geiser,
Vinicio A. de Jesus Perez,
Wolfgang M. Kuebler,
Soheila Zeinali,
Olivier T. Guenat
Affiliations
Dario Ferrari
Organs-on-chip Technologies Laboratory, ARTORG Center, University of Bern, Bern, Switzerland
Arunima Sengupta
Organs-on-chip Technologies Laboratory, ARTORG Center, University of Bern, Bern, Switzerland
Lyong Heo
Stanford Center for Genomics and Personalized Medicine, Palo Alto, CA, USA
Laszlo Pethö
Empa, Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Mechanics of Materials and Nanostructures, Thun, Switzerland
Johann Michler
Empa, Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Mechanics of Materials and Nanostructures, Thun, Switzerland
Thomas Geiser
Department of Pulmonary Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
Vinicio A. de Jesus Perez
Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University Medical Center, Stanford, CA, USA
Wolfgang M. Kuebler
Institute of Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Soheila Zeinali
Organs-on-chip Technologies Laboratory, ARTORG Center, University of Bern, Bern, Switzerland
Olivier T. Guenat
Organs-on-chip Technologies Laboratory, ARTORG Center, University of Bern, Bern, Switzerland; Department of Pulmonary Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland; Department of General Thoracic Surgery, Inselspital, University Hospital of Bern, Bern, Switzerland; Corresponding author
Summary: The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli. Here, we present a microvasculature-on-chip model to investigate the singular effect of ECM stiffness and mechanical cyclic stretch on vascular development. Following two different approaches for vascular growth, the effect of ECM stiffness on sprouting angiogenesis and the effect of cyclic stretch on endothelial vasculogenesis are studied. Our results indicate that ECM hydrogel stiffness controls the size of the patterned vasculature and the density of sprouting angiogenesis. RNA sequencing shows that the cellular response to stretching is characterized by the upregulation of certain genes such as ANGPTL4+5, PDE1A, and PLEC.
