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Mechanotransductive feedback control of endothelial cell motility and vascular morphogenesis

Devon E. Mason, Megan Goeckel, Sebastián L. Vega, Pei-Hsun Wu, Dymonn Johnson, Su-Jin Heo, Denis Wirtz, Jason A. Burdick, Levi Wood, Brian Y. Chow, View ORCID ProfileAmber N. Stratman, View ORCID ProfileJoel D. Boerckel
doi: https://doi.org/10.1101/2022.06.15.496293
Devon E. Mason
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA
2Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Megan Goeckel
3Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO
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Sebastián L. Vega
2Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
4Department of Biomedical Engineering, Rowan University, Glassboro, NJ
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Pei-Hsun Wu
5Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD
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Dymonn Johnson
3Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO
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Su-Jin Heo
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA
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Denis Wirtz
5Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD
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Jason A. Burdick
2Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Levi Wood
6George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA
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Brian Y. Chow
2Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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Amber N. Stratman
3Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO
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  • ORCID record for Amber N. Stratman
  • For correspondence: a.stratman@wustl.edu boerckel@pennmedicine.upenn.edu
Joel D. Boerckel
1McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA
2Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
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  • ORCID record for Joel D. Boerckel
  • For correspondence: a.stratman@wustl.edu boerckel@pennmedicine.upenn.edu
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Abstract

Vascular morphogenesis requires persistent endothelial cell motility that is responsive to diverse and dynamic mechanical stimuli. Here, we interrogated the mechanotransductive feedback dynamics that govern endothelial cell motility and vascular morphogenesis. We show that the transcriptional regulators, YAP and TAZ, are activated by mechanical cues to transcriptionally limit cytoskeletal and focal adhesion maturation, forming a conserved mechanotransductive feedback loop that mediates human endothelial cell motility in vitro and zebrafish intersegmental vessel (ISV) morphogenesis in vivo. This feedback loop closes in 4 hours, achieving cytoskeletal equilibrium in 8 hours. Feedback loop inhibition arrested endothelial cell migration in vitro and ISV morphogenesis in vivo. Inhibitor washout at 3 hrs, prior to feedback loop closure, restored vessel growth, but washout at 8 hours, longer than the feedback timescale, did not, establishing lower and upper bounds for feedback kinetics in vivo. Mechanistically, YAP and TAZ induced transcriptional suppression of myosin II activity to maintain dynamic cytoskeletal equilibria. Together, these data establish the mechanoresponsive dynamics of a transcriptional feedback loop necessary for persistent endothelial cell migration and vascular morphogenesis.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 16, 2022.
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Mechanotransductive feedback control of endothelial cell motility and vascular morphogenesis
Devon E. Mason, Megan Goeckel, Sebastián L. Vega, Pei-Hsun Wu, Dymonn Johnson, Su-Jin Heo, Denis Wirtz, Jason A. Burdick, Levi Wood, Brian Y. Chow, Amber N. Stratman, Joel D. Boerckel
bioRxiv 2022.06.15.496293; doi: https://doi.org/10.1101/2022.06.15.496293
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Mechanotransductive feedback control of endothelial cell motility and vascular morphogenesis
Devon E. Mason, Megan Goeckel, Sebastián L. Vega, Pei-Hsun Wu, Dymonn Johnson, Su-Jin Heo, Denis Wirtz, Jason A. Burdick, Levi Wood, Brian Y. Chow, Amber N. Stratman, Joel D. Boerckel
bioRxiv 2022.06.15.496293; doi: https://doi.org/10.1101/2022.06.15.496293

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