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J Clin Invest. 2019 Oct 22. pii: 122767. doi: 10.1172/JCI122767. [Epub ahead of print]

Caspase-8 modulates physiological and pathological angiogenesis during retina development.

Author information

1
Biochemistry Center.
2
European Center for Angioscience (ECAS).
3
Institute for Transfusion Medicine and Immunology, Medical Faculty Mannheim, and.
4
Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.
5
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla and Universidad Pablo de Olavide, Sevilla, Spain.
6
Division of Vascular Oncology and Metastasis, German Cancer Research Center, Heidelberg, Germany.
7
Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (VIB), Leuven, Belgium.
8
Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
9
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
10
Development and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
11
Department of Medical Biology, University of Melbourne, Melbourne, Australia.
12
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
13
Department of Cellular and Molecular Pathology and.
14
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
15
Institute of Pathology, TUM School of Medicine, Technical University of Munich, Munich, Germany.
16
Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
17
Faculty of Medicine and.
18
Research Laboratory, Department of Ophthalmology, University Medical Center, University of Münster, Münster, Germany.
19
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
20
Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Carlos III Health Institute, Madrid, Spain.

Abstract

During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel formation are still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-8ECKO) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.

KEYWORDS:

Angiogenesis; Apoptosis pathways; Caspases and caspase substrates; Retinopathy

PMID:
31454332
DOI:
10.1172/JCI122767
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