Thromb Haemost 2017; 117(06): 1150-1163
DOI: 10.1160/TH16-05-0354
Endothelium and Angiogenesis
Schattauer GmbH

Endogenous developmental endothelial locus-1 limits ischaemia- related angiogenesis by blocking inflammation

Anne Klotzsche - von Ameln
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Sebastian Cremer
2  Department of Internal Medicine III, Cardiology; Goethe University Frankfurt, Germany
,
Jedrzej Hoffmann
2  Department of Internal Medicine III, Cardiology; Goethe University Frankfurt, Germany
,
Peggy Schuster
3  Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany
,
Sherif Khedr
4  Institute of Physiology, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Irina Korovina
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Maria Troullinaki
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Ales Neuwirth
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
David Sprott
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Antonios Chatzigeorgiou
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Matina Economopoulou
5  Department of Ophthalmology, Technische Universität Dresden, Dresden, Germany
6  DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
,
Alessia Orlandi
3  Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany
,
Andreas Hain
3  Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany
,
Andreas M. Zeiher
2  Department of Internal Medicine III, Cardiology; Goethe University Frankfurt, Germany
7  German Center of Cardiovascular Research (DZHK), RheinMain Partner Site, Frankfurt, Germany
,
Andreas Deussen
4  Institute of Physiology, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
George Hajishengallis
8  Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
,
Stefanie Dimmeler
3  Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany
7  German Center of Cardiovascular Research (DZHK), RheinMain Partner Site, Frankfurt, Germany
,
Triantafyllos Chavakis
1  Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany
6  DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
,
Emmanouil Chavakis
2  Department of Internal Medicine III, Cardiology; Goethe University Frankfurt, Germany
3  Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany
7  German Center of Cardiovascular Research (DZHK), RheinMain Partner Site, Frankfurt, Germany
› Author Affiliations
Financial support: This work was supported by the Else Kröner-Fresenius-Stiftung (2013_A2 to E. C.). E. C. and S. D. are members of the Excellence Cluster Cardiopulmonary System (DFG; Exc147–1), the German Centre for Cardiovascular Research (BMBF) and the LOEWE Center for Gene and Cell Therapy (Hessen, Germany). S. C. is also supported by a grant from the LOEWE Center for Gene and Cell Therapy. T.C. was supported by the ERC (ENDHOMRET), the DFG (INST 515/11–1) and DE026152 from the NIH. M.E. was supported by the Else Kröner-Fresenius-Stiftung. G.H. was supported by DE026152, DE024716 and DE015254 from the NIH. S.K. was supported by a Grant of DAAD (Deutscher Akademischer Austauschdienst).
Further Information

Publication History

Received: 12 May 2016

Accepted after major revision: 05 March 2017

Publication Date:
28 November 2017 (online)

Summary

We have recently identified endothelial cell-secreted developmental endothelial locus-1 (Del-1) as an endogenous inhibitor of β2-integrin–dependent leukocyte infiltration. Del-1 was previously also implicated in angiogenesis. Here, we addressed the role of endogenously produced Del-1 in ischaemia-related angiogenesis. Intriguingly, Del-1–deficient mice displayed increased neovascularisation in two independent ischaemic models (retinopathy of prematurity and hind-limb ischaemia), as compared to Del-1–proficient mice. On the contrary, angiogenic sprouting in vitro or ex vivo (aortic ring assay) and physiological developmental retina angiogenesis were not affected by Del-1 deficiency. Mechanistically, the enhanced ischaemic neovascularisation in Del-1-deficiency was linked to higher infiltration of the ischaemic tissue by CD45+ haematopoietic and immune cells. Moreover, Del-1-deficiency promoted β2-integrin–dependent adhesion of haematopoietic cells to endothelial cells in vitro, and the homing of hematopoietic progenitor cells and of immune cell populations to ischaemic muscles in vivo. Consistently, the increased hind limb ischaemia-related angiogenesis in Del-1 deficiency was completely reversed in mice lacking both Del-1 and the β2-integrin LFA-1. Additionally, enhanced retinopathy-associated neovascularisation in Del-1-deficient mice was reversed by LFA-1 blockade. Our data reveal a hitherto unrecognised function of endogenous Del-1 as a local inhibitor of ischaemia-induced angiogenesis by restraining LFA-1–dependent homing of pro-angiogenic haematopoietic cells to ischaemic tissues. Our findings are relevant for the optimisation of therapeutic approaches in the context of ischaemic diseases.

Supplementary Material to this article is available online at www.thrombosis-online.com.