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 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 1

Postnatal EC-specific KO of Casp-8 results in impaired angiogenesis.

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Postnatal EC-specific KO of Casp-8 results in impaired angiogenesis. (A)...
(A) Schematic showing tamoxifen administration in pups. (B) Representative images of whole-mount P6 retinas stained with IsoB4 (ECs) in Casp-8WT and Casp-8ECKO mice. Dashed black lines highlight the total retina area. (C and D) Quantification of vessel area (C; n = 22 WT, n = 21 ECKO) and retina vessel outgrowth (D; n = 20 WT, n = 20 ECKO). (E) Representative higher magnifications of the retina stained with IsoB4. (F) Quantification of number of branches (n = 18 WT, n = 16 ECKO). (G) Representative images of the retina angiogenic front stained with IsoB4. Black arrows point to EC sprouts. (H) Quantification of the number of sprouts per front length showing reduced number of sprouts in Casp-8ECKO retinas (n = 16 WT, n = 12 ECKO). For C, D, F, and H, data are shown as mean ± SEM from 4 independent litters. *P < 0.05; ***P < 0.001, 2-tailed unpaired Student’s t test. Scale bars: 100 μm (B); 50 μm (E); 20 μm (G).