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Caspase-8 modulates physiological and pathological angiogenesis during retina development.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 Dec 02; Vol. 129 (12), pp. 5092-5107. - Publication Year :
- 2019
-
Abstract
- During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is 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.
- Subjects :
- Animals
Animals, Newborn
Antigens, CD metabolism
Cadherins metabolism
Cell Death
Cell Movement
Cell Proliferation
Endothelial Cells metabolism
Female
Human Umbilical Vein Endothelial Cells
Humans
Lung embryology
Mice
Mice, Knockout
Necroptosis
Oxygen metabolism
Phosphorylation
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Signal Transduction
p38 Mitogen-Activated Protein Kinases metabolism
Caspase 8 metabolism
Neovascularization, Pathologic
Neovascularization, Physiologic
Retina embryology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 31454332
- Full Text :
- https://doi.org/10.1172/JCI122767