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Caspase-8 modulates physiological and pathological angiogenesis during retina development


Tisch, N; Freire-Valls, A; Yerbes, R; Paredes, I; La Porta, S; Wang, X; Martin-Perez, R; Castro, L; Wong, WW; Coultas, L; Strilic, B; Grone, HJ; Hielscher, T; Mogler, C; Adams, RH; Heiduschka, P; Claesson-Welsh, L; Mazzone, M; Lopez-Rivas, A; Schmidt, T; Augustin, HG; Ruiz de Almodovar, C
2019-12-02
Journal of Clinical Investigation
Journal Article
129
12
5092-5107
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.
Am Soc Clin Invest
Epigenetics and Development
10.1172/JCI122767
31454332
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2019-12-16 02:49:02 Last Modified 2019-12-16 03:05:26