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EBioMedicine. 2018 Jan;27:237-246. doi: 10.1016/j.ebiom.2017.11.020. Epub 2017 Nov 26.

Midkine Controls Arteriogenesis by Regulating the Bioavailability of Vascular Endothelial Growth Factor A and the Expression of Nitric Oxide Synthase 1 and 3.

Author information

1
Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 81377 Munich, Germany; Biomedical Center, LMU Munich, 81377 Munich, Germany.
2
Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 81377 Munich, Germany.
3
Department of Vascular and Endovascular Surgery, Goethe-University-Hospital, 60590 Frankfurt am Main, Germany; Division of Arteriogenesis Research, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
4
Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 81377 Munich, Germany; Hospital of the University of Munich, Department of Anesthesiology, LMU Munich, 81377 Munich, Germany.
5
Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, 81377 Munich, Germany; Biomedical Center, LMU Munich, 81377 Munich, Germany. Electronic address: Elisabeth.Deindl@med.uni-muenchen.de.

Abstract

Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation. The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.

KEYWORDS:

Arteriogenesis; Endothelial nitric oxide synthase; Midkine; Neuronal nitric oxide synthase; Vascular endothelial growth factor A; Vascular endothelial growth factor receptor 2

PMID:
29233575
PMCID:
PMC5828057
DOI:
10.1016/j.ebiom.2017.11.020
[Indexed for MEDLINE]
Free PMC Article

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