Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia

Ministro, Augusto; Oliveira, Paula de; Nunes, Ricardo Rodrigues; Rocha, André Alexandre Dos Santos; Correia, Adriana; Carvalho, Tânia; Rino, José Pedro; Faísca, Pedro; Becker, Jörg; Goyri-O’Neill, João; Pina, Maria de Fátima de; Poli, E.; Silva‐Santos, Bruno; Pinto, Fausto J.; Mareel, Marc; Serre, Karine; Santos, Susana Constantino Rosa

doi:10.1093/cvr/cvx065

Cited by 26 publications

(39 citation statements)

References 20 publications

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“…Consistently, in the presence of a VEGFR tyrosine kinase inhibitor, the effect observed upon LDIR exposure was abrogated, which was further validated using animal models 10,11 . In a hindlimb ischemia model, we demonstrated that angiogenesis and arteriogenesis was enhanced by LDIR and consequently neovascularization was induced 10 . In particular, using a zebrafish model we observed that LDIR induced vessel formation in the sub-intestinal vessels during post-embryonic development.…”

supporting

confidence: 55%

“…In consequence, the activation of PI3K/AKT and ERK/MAPK signaling pathways was observed and the expression of 2374 genes was modulated by LDIR 11 in human microvasculature. Interestingly, 1344 of those genes, including angiogenic ones, have their expression significantly increased after LDIR exposure 10 .…”

Section: Discussionmentioning

confidence: 99%

“…Since we showed that doses lower or equal to 0.8 Gy induce angiogenesis both in vitro 11 , in different animal models 10,11 and in human 26 , we decided to consider this dose range and investigate the effect of doses lower or higher than 0.5 Gy in the zebrafish post-embryonic development. With the aim to investigate the effect of doses lower and higher than 0.5, Fli1:EGFP zebrafish larvae were exposed or not to 0.3 or 0.8 Gy, during three consecutive days and photographed over time.…”

Section: Ldir Significantly Increase the Expression Of Several Pro-anmentioning

confidence: 99%

“…(VEGFR), which consequently activates multiple signaling pathways and enhances a pro-angiogenic response. The endothelial gene expression profile showed a significant modulation by LDIR, where several receptors and proteins associated with a pro-angiogenic response were significantly up-regulated 10 . Consistently, in the presence of a VEGFR tyrosine kinase inhibitor, the effect observed upon LDIR exposure was abrogated, which was further validated using animal models 10,11 .…”

mentioning

confidence: 99%

“…The endothelial gene expression profile showed a significant modulation by LDIR, where several receptors and proteins associated with a pro-angiogenic response were significantly up-regulated 10 . Consistently, in the presence of a VEGFR tyrosine kinase inhibitor, the effect observed upon LDIR exposure was abrogated, which was further validated using animal models 10,11 . In a hindlimb ischemia model, we demonstrated that angiogenesis and arteriogenesis was enhanced by LDIR and consequently neovascularization was induced 10 .…”

mentioning

confidence: 99%

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Low doses of ionizing radiation enhance angiogenesis and consequently accelerate post-embryonic development but not regeneration in zebrafish

Marques

Carvalho

Sousa

et al. 2020

Sci Rep

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Low doses of ionizing radiation (LDIR) activate endothelial cells inducing angiogenesis. In zebrafish,LDiR induce vessel formation in the sub-intestinal vessels during post-embryonic development and enhance the inter-ray vessel density in adult fin regeneration. Since angiogenesis is a crucial process involved in both post-embryonic development and regeneration, herein we aimed to understand whether LDiR accelerate these physiological conditions. our data show that LDiR upregulate the gene expression of several pro-angiogenic molecules, such as flt1, kdr, angpt2a, tgfb2, fgf2 and cyr61in sorted endothelial cells from zebrafish larvae and this effect was abrogated by using a vascular endothelial growth factor receptor (VEGFR)-2 tyrosine kinase inhibitor. Irradiated zebrafish present normal indicators of developmental progress but, importantly LDiR accelerate post-embryonic development in a VEGFR-2 dependent signaling. Furthermore, our data show that LDIR do not accelerate regeneration after caudal fin amputation and the gene expression of the early stages markers of regeneration are not modulated by LDiR. even though regeneration is considered as a recapitulation of embryonic development and LDIR induce angiogenesis in both conditions, our findings show that LDiR accelerate post-embryonic development but not regeneration. this highlights the importance of the physiological context for a specific phenotype promoted by LDIR.

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confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Ldir Significantly Increase the Expression Of Several Pro-anmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Low doses of ionizing radiation enhance angiogenesis and consequently accelerate post-embryonic development but not regeneration in zebrafish

Marques

Carvalho

Sousa

et al. 2020

Sci Rep

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Hydrogel Loaded with VEGF/TFEB‐Engineered Extracellular Vesicles for Rescuing Critical Limb Ischemia by a Dual‐Pathway Activation Strategy

Zheng

Zhao

et al. 2021

Adv Healthcare Materials

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Critical limb ischemia (CLI) is the most severe clinical manifestation of peripheral arterial disease, which causes many amputations and deaths. Conventional treatment strategies for CLI (e.g., stent implantation and vascular surgery) bring surgical risk, which are not suitable for each patient. Extracellular vesicles (EVs) can be a potential solution for CLI. Herein, vascular endothelial growth factor (VEGF; i.e., a crucial molecule related to angiogenesis) and transcription factor EB (TFEB; i.e., a pivotal regulator of autophagy) are chosen as the target gene to improve the bioactivity of EVs derived from endothelial cells. The VEGF/TFEB-engineered EVs (Engineered-EVs) are fabricated by genetically engineering the parent cells, and their versatile functions are confirmed using three cell models (human umbilical vein endothelial cells, myoblast, and monocytes). Injectable thermal-responsive hydrogel are then combined with Engineered-EVs to combat CLI. These results reveal that the hydrogel can enhance the stability of Engineered-EVs in vivo and release EVs at different temperatures. Moreover, the results of animal studies indicate that Engineered-EV/Hydrogel can significantly improve neovascularization, attenuate muscle injury, and recover limb function after CLI. Finally, mechanistic studies shed light on the therapeutic effect of Engineered-EV/Hydrogel due to the activated VEGF/VEGFR pathway and autophagy-lysosomal pathway.

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Radio-Immunology of Ablative Radiation

Savage

Guha

2019

Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy

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Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia

Abstract: These findings disclose an innovative, non-invasive strategy to induce therapeutic neovascularization in a mouse model of HLI, emerging as a novel approach in the treatment of critical limb ischemia patients.

Cited by 26 publications

References 20 publications

Low doses of ionizing radiation enhance angiogenesis and consequently accelerate post-embryonic development but not regeneration in zebrafish

Low doses of ionizing radiation enhance angiogenesis and consequently accelerate post-embryonic development but not regeneration in zebrafish

Hydrogel Loaded with VEGF/TFEB‐Engineered Extracellular Vesicles for Rescuing Critical Limb Ischemia by a Dual‐Pathway Activation Strategy

Radio-Immunology of Ablative Radiation

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