期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 12, 页码 5092-5107出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI122767
关键词
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资金
- Nikon imaging Center of the University of Heidelberg
- Heidelberg Biosciences International Graduate School (HBIGS) PhD fellowship
- Becas Chile
- Alexander Von Humboldt postdoctoral fellowship
- Deutsche Forschungsgemeinschaft (DFG) [SCHM 2560/3-1, RU 1990/1-1, SFB873, FOR2325, SFB1366, 394046768-SFB 1366]
- ERC [ERC-StG-311367]
- National Health and Research Council (NHMRC) [1125536]
- L.E.W. Carty Charitable Fund
- National Health and Medical Research Council of Australia [1125536] Funding Source: NHMRC
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-8(ECKO)) 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.
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