Caspase-8 modulates physiological and pathological angiogenesis during retina development
Nathalie Tisch, … , Hellmut G. Augustin, Carmen Ruiz de Almodovar
Nathalie Tisch, … , Hellmut G. Augustin, Carmen Ruiz de Almodovar
Published December 2, 2019; First published August 27, 2019
Citation Information: J Clin Invest. 2019;129(12):5092-5107. https://doi.org/10.1172/JCI122767.
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Research Article Angiogenesis

Caspase-8 modulates physiological and pathological angiogenesis during retina development

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.

Authors

Nathalie Tisch, Aida Freire-Valls, Rosario Yerbes, Isidora Paredes, Silvia La Porta, Xiaohong Wang, Rosa Martín-Pérez, Laura Castro, Wendy Wei-Lynn Wong, Leigh Coultas, Boris Strilic, Hermann-Josef Gröne, Thomas Hielscher, Carolin Mogler, Ralf H. Adams, Peter Heiduschka, Lena Claesson-Welsh, Massimiliano Mazzone, Abelardo López-Rivas, Thomas Schmidt, Hellmut G. Augustin, Carmen Ruiz de Almodovar

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Figure 4

Casp-8 is necessary for maintaining EC junction stability at the retina plexus in vivo.

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Casp-8 is necessary for maintaining EC junction stability at the retina ...
(A) Representative images of Casp-8WT and Casp-8ECKO retinas stained with IsoB4, VE-cadherin, and claudin-5 (insets of left panels are shown on the adjacent right panels), showing that junctions are more serrated and discontinuous at the retina plexus in Casp-8ECKO compared with Casp-8WT mice (yellow arrows). Images of VE-cadherin and Claudin-5 single channels were transformed to gray colors with ImageJ for better visualization. (B) Quantification of the percentage of VE-cadherin patches showing a significant increase in the number of highly active VE-cadherin patches and a lower number of highly inhibited patches in Casp-8ECKO compared with Casp-8WT mice. Each box shows the median percentage of patches of that type (line) and upper and lower quartiles (box). The whiskers extend to the most extreme data within 1.5 times the interquartile range of the box. *P < 0.05; **P < 0.01, Dirichlet regression model with 2-tailed Mann-Whitney U test for each state. n = 9 WT, n = 9 ECKO. (C) Average of the differential distribution of the percentage of VE-cadherin patches in Casp-8WT and Casp-8ECKO retinas. Scale bars: 20 μm (A).