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Endothelial Cells Control Muscle Regeneration Through Angiocrine Lactate

60 Pages Posted: 3 Jan 2020 Sneak Peek Status: Review Complete

See all articles by Jing Zhang

Jing Zhang

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Jonathan Muri

ETH Zürich - Institute of Molecular Health Sciences

Tatiane Gorski

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Gillian Fitzgerald

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Gommaar D'Hulst

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zheng Fan

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Mélanie Planque

University of Leuven, Biomedical Sciences Group, Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism; KU Leuven, VIB Center for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism

Peter Carmeliet

University of Leuven, Biomedical Sciences Group, Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism; KU Leuven, VIB Center for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism

Sarah-Maria Fendt

KU Leuven - Laboratory of Cellular Metabolism and Metabolic Regulation

Inés Soro-Arnaiz

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Manfred Kopf

ETH Zürich - Institute of Molecular Health Sciences

Katrien De Bock

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

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Abstract

Endothelial cell (EC) derived angiocrine signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Adding lactate to conditioned medium from pfkfb3-deficient ECs rescued M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Macrophages also secreted more VEGF, thereby creating a positive feedback loop that further stimulates angiogenesis. Finally, increasing lactate levels during ischemia sufficed to rescue macrophage polarization, resulting in improved muscle reperfusion and regeneration. In summary, ECs exploit their glycolytic capacity for angiocrine lactate shuttling to steer muscle regeneration from ischemia.

Keywords: angiogenesis, metabolism, angriocrine signals, lactate, ischemia, macrophage polarisation, muscle regeneration

Suggested Citation

Zhang, Jing and Muri, Jonathan and Gorski, Tatiane and Fitzgerald, Gillian and D'Hulst, Gommaar and Fan, Zheng and Planque, Mélanie and Carmeliet, Peter and Fendt, Sarah-Maria and Soro-Arnaiz, Inés and Kopf, Manfred and De Bock, Katrien, Endothelial Cells Control Muscle Regeneration Through Angiocrine Lactate (December 24, 2019). Available at SSRN: https://ssrn.com/abstract=3508871 or http://dx.doi.org/10.2139/ssrn.3508871
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jing Zhang

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

Jonathan Muri

ETH Zürich - Institute of Molecular Health Sciences

Zürichbergstrasse 18
8092 Zurich, CH-1015
Switzerland

Tatiane Gorski

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

Gillian Fitzgerald

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

Gommaar D'Hulst

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

Zheng Fan

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

Mélanie Planque

University of Leuven, Biomedical Sciences Group, Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism

Leuven
Belgium

KU Leuven, VIB Center for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism

Leuven
Belgium

Peter Carmeliet

University of Leuven, Biomedical Sciences Group, Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism

Celestijnenlaan 200F
B-3001
Leuven
Belgium

KU Leuven, VIB Center for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism

Leuven
Belgium

Sarah-Maria Fendt

KU Leuven - Laboratory of Cellular Metabolism and Metabolic Regulation

Leuven
Belgium

Inés Soro-Arnaiz

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

Manfred Kopf

ETH Zürich - Institute of Molecular Health Sciences

Zürichbergstrasse 18
8092 Zurich, CH-1015
Switzerland

Katrien De Bock (Contact Author)

Swiss Federal Institute of Technology Zurich, Department of Health Sciences and Technology, Laboratory of Exercise and Health

Zurich
Switzerland

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