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

Authors :
Tisch N
Freire-Valls A
Yerbes R
Paredes I
La Porta S
Wang X
Martín-Pérez R
Castro L
Wong WW
Coultas L
Strilic B
Gröne HJ
Hielscher T
Mogler C
Adams RH
Heiduschka P
Claesson-Welsh L
Mazzone M
López-Rivas A
Schmidt T
Augustin HG
Ruiz de Almodovar C
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.

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