Research Publications


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
Journal of Clinical Investigation
Journal Article
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
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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