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Title

Caspase-8 modulates physiological and pathological angiogenesis during retina development

AuthorsTisch, Nathalie; Freire-Valls, Aida; Yerbes, Rosario ; Paredes, Isadora; La Porta, Silvia; Wang, Xiaohong; Martín-Pérez, Rosa ; Castro, Laura; Wong, Wendy Wei-Lynn; Coultas, Leigh; Strilic, Boris; Gröne, Hermann-Josef; Hielscher, Thomas; Mogler, Carolin; Adams, Ralf H.; Heiduschka, Peter; Claesson-Welsh, Lena; Mazzone, Massimiliano; López-Rivas, Abelardo ; Schmidt, Thomas; Augustin, Hellmut G.; Ruiz de Almodóvar, Carmen
Issue DateDec-2019
PublisherAmerican Society for Clinical Investigation
CitationJournal of Clinical Investigation 129(12): 5092-5107 (2019)
AbstractDuring 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-8) 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-8 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.
Publisher version (URL)http://dx.doi.org/10.1172/JCI122767
URIhttp://hdl.handle.net/10261/207539
Identifiersdoi: 10.1172/JCI122767
e-issn: 1558-8238
issn: 0021-9738
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