Caspase-8 modulates physiological and pathological angiogenesis during retina development

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

doi:10.1172/jci122767

Cited by 23 publications

(21 citation statements)

References 74 publications

(89 reference statements)

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“…MLKL knockout mice are healthy and viable and show no vascular defects ( Supplementary Fig. S4), suggesting that MLKL is not necessary for physiological vascular development 36,37 . Instead, MLKL regulated adhesion molecule expression at the post-transcriptional level by increasing mRNA stability upon TNFα stimulation.…”

Section: Discussionmentioning

confidence: 99%

A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression

et al. 2020

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Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation.

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Section: Discussionmentioning

confidence: 99%

A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression

et al. 2020

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“…In vitro BrdU incorporation was performed as described 71 . Briefly, 2×10 4 HUVECs were cultured in collagen coated coverslips in 24-well plates and pretreated with EXO, KV11 or EXO KV11 (KV11-CP05 and EXO were incubated for 6 h at 4 °C before treatment) at concentration of 12.5 μg/mL EXO and 25 μg/mL peptide for 24 h in starvation medium.…”

Section: Methods Detailsmentioning

confidence: 99%

“…Angiogenesis is vital for embryonic development 1 , 2 , and abnormal blood vessel growth contributes to many diseases, such as tumors and neovascular eye diseases 3 , 4 . Pathological retinal neovascularization is a key pathological change in diseases such as retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), which are the major causes of vision loss in preterm infants and working-age adults 5 - 7 . Abnormal blood vessel growth is also characterized by compromised blood-retinal barrier (BRB) function, which further leads to hemorrhage, retinal detachment, and eventually blindness 8 .…”

Section: Introductionmentioning

confidence: 99%

Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis

Dong¹,

Lee²,

Yu³

et al. 2021

Theranostics

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Background: Pathological angiogenesis is the hallmark of many vision-threatening diseases. Anti-VEGF is a primary treatment with substantial beneficial effects. However, such agents require frequent intravitreal injections. Our previous work established a method for effectively modifying exosomes (EXOs) for loading therapeutic peptides. Here, we used this system to load the anti-angiogenic peptide KV11, aiming to establish an EXO-based therapy strategy to suppress neovascularization in the retina. Methods: Using an anchoring peptide, CP05, we linked KV11 to endothelial cell (EC) derived EXOs, yielding EXO KV11 . We tested the delivery efficiency of EXO KV11 via two commonly used ocular injection methods: retro-orbital injection and intravitreal injection. Deploying an oxygen-induced retinopathy (OIR) model and a VEGF injection model, we tested the effects of EXO KV11 on neovascular formation, EC proliferation, and vascular permeability. In vitro experiments were used to test the mechanism and to analyze the effects of EXO KV11 on EC proliferation, migration, and sprouting. Results : By using the EXO loading system, KV11 was more efficiently delivered to the blood vessels of the mouse retina via retro-orbital injection. In both OIR model and VEGF injection model, EXO KV11 was more effective than KV11 alone in inhibiting neovascularization and vessel leakage. The therapeutic effect of retro-orbital injection of EXO KV11 was comparable to the intravitreal injection of VEGF-trap. Mechanistically, KV11 alone inhibited VEGF-downstream signaling, while EXO KV11 showed a stronger effect. Conclusions: We used EXOs as a carrier for intraocular delivery of KV11. We showed that KV11 itself has an anti-angiogenic effect through retro-orbital injection, but that this effect was greatly enhanced when delivered with EXOs. Thus, this system has the potential to treat proliferative retinopathy via retro-orbital injection which is a less invasive manner compared with intravitreal injection.

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“…These defects are rescued when either apoptosis or necroptosis are inhibited, as shown in double or triple knockout mice like c-FLIP ko /FADD ko /RIPK3 ko [ 59 ], Casp8 ko /RIPK3 ko [ 60 ] or Casp8/MLKL ko [ 61 ] mice. In particular, EC-specific deletion of Casp8 [ 13 , 62 ], FADD [ 63 ] and other pro-survival molecules [ 55 , 64 ] of the extrinsic cell death signaling pathway recapitulates the severity of the full knockout of these genes, indicating that pro-survival molecules of the extrinsic cell death signaling pathway are required to promote EC survival during embryonic development. Additionally, a pro-survival role for the heterodimer of CASP-8 and c-FLIP was described in multiple other tissues in vivo [ 59 ].…”

Section: Regulation Of Cell Death During Development Of the Embryonicmentioning

confidence: 99%

“…Whereas it is undoubted that EC death contributes to the complete removal of certain vascular networks during development, such as the hyaloid vasculature of the fetal retina [7][8][9] or the first, second and fifth aortic arches [10,11] during the formation of the cardiovascular system, it seems that cell death is not a key driver for later stages of vessel pruning, when vessel branches only partially regress to improve the functionality of an existing vascular network [12]. Recent evidences suggest that under such conditions, the activity of the cell death signaling machinery can even promote angiogenesis and blood vessel development [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Contribution of cell death signaling to blood vessel formation

Tisch

Almodóvar

2021

Cell. Mol. Life Sci.

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The formation of new blood vessels is driven by proliferation of endothelial cells (ECs), elongation of maturing vessel sprouts and ultimately vessel remodeling to create a hierarchically structured vascular system. Vessel regression is an essential process to remove redundant vessel branches in order to adapt the final vessel density to the demands of the surrounding tissue. How exactly vessel regression occurs and whether and to which extent cell death contributes to this process has been in the focus of several studies within the last decade. On top, recent findings challenge our simplistic view of the cell death signaling machinery as a sole executer of cellular demise, as emerging evidences suggest that some of the classic cell death regulators even promote blood vessel formation. This review summarizes our current knowledge on the role of the cell death signaling machinery with a focus on the apoptosis and necroptosis signaling pathways during blood vessel formation in development and pathology.

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Caspase-8 modulates physiological and pathological angiogenesis during retina development

Cited by 23 publications

References 74 publications

A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression

A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression

Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis

Contribution of cell death signaling to blood vessel formation

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