TY  - JOUR
AU  - Tisch, Nathalie
AU  - Freire-Valls, Aida
AU  - Yerbes, Rosario
AU  - Paredes, Isidora
AU  - La Porta, Silvia
AU  - Wang, Xiaohong
AU  - Martín-Pérez, Rosa
AU  - Castro, Laura
AU  - Wong, Wendy Wei-Lynn
AU  - Coultas, Leigh
AU  - Strilic, Boris
AU  - Gröne, Hermann-Josef
AU  - Hielscher, Thomas
AU  - Mogler, Carolin
AU  - Adams, Ralf
AU  - Heiduschka, Peter
AU  - Claesson-Welsh, Lena
AU  - Mazzone, Massimiliano
AU  - López-Rivas, Abelardo
AU  - Schmidt, Thomas
AU  - Augustin, Hellmut G
AU  - Ruiz de Almodovar, Carmen
TI  - Caspase-8 modulates physiological and pathological angiogenesis during retina development.
JO  - The journal of clinical investigation
VL  - 129
IS  - 12
SN  - 1558-8238
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2019-02294
SP  - 5092-5107
PY  - 2019
N1  -  2019 Dec 2;129(12):5092-5107
AB  - 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 is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates both cell death via apoptosis and necroptosis. Here we show that expression of Casp-8 in endothelial cells (ECs) was required for proper postnatal retina angiogenesis. EC specific Casp-8 knockout pups (Casp-8ECko) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting and migration independent of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 mitogen-activated protein kinase (MAPK) downstream of receptor-interacting serine/threonine- protein kinase 3 (RIPK3) and destabilization of 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. Taken together, we describe 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31454332
DO  - DOI:10.1172/JCI122767
UR  - https://inrepo02.dkfz.de/record/144870
ER  -