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Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia.

ABSTRACT: Critical limb ischemia is the most serious form of peripheral artery disease, characterized by severe functional consequences, difficult clinical management and reduced life expectancy. The goal of this study was to investigate the miR-210 role in the neo-angiogenic response after acute limb ischemia. Complementary approaches were used in a mouse model of hindlimb ischemia: miR-210 loss-of-function was obtained by administration of LNA-oligonucleotides anti-miR-210; for miR-210 gain-of-function, a doxycycline-inducible miR-210 transgenic mouse was used. We tested miR-210 ability to stimulate vascular regeneration following ischemia. We found that miR-210 was necessary and sufficient to stimulate blood perfusion recovery, as well as arteriolar and capillary density increase, in the ischemic muscle. To clarify the molecular events underpinning miR-210 pro-angiogenic action, the transcriptomic changes in ischemic muscles upon miR-210 blocking were analyzed. We found that miR-210 impacted the transcriptome significantly, regulating pathways and functions linked to vascular regeneration. In agreement with a pro-angiogenic role, miR-210 also improved cardiac function and left ventricular remodeling after myocardial infarction. Moreover, miR-210 blocking decreased capillary density in a Matrigel plug assay, indicating that miR-210 is necessary for angiogenesis independently of ischemia. Collectively, these data indicate that miR-210 plays a pivotal role in promoting vascular regeneration.

SUBMITTER: Zaccagnini G

PROVIDER: S-EPMC6981725 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia.

Zaccagnini Germana G Maimone Biagina B Fuschi Paola P Longo Marialucia M Da Silva Daniel D Carrara Matteo M Voellenkle Christine C Perani Laura L Esposito Antonio A Gaetano Carlo C Martelli Fabio F

International journal of molecular sciences 20191224 1

Critical limb ischemia is the most serious form of peripheral artery disease, characterized by severe functional consequences, difficult clinical management and reduced life expectancy. The goal of this study was to investigate the miR-210 role in the neo-angiogenic response after acute limb ischemia. Complementary approaches were used in a mouse model of hindlimb ischemia: miR-210 loss-of-function was obtained by administration of LNA-oligonucleotides anti-miR-210; for miR-210 gain-of-function, ...[more]

PMID: 31878120

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Project description:Hypoxia-induced miR-210 is a crucial component of the tissue response to ischemia, stimulating angiogenesis and improving tissue regeneration. Previous analysis of miR-210 impact on the transcriptome in a mouse model of hindlimb ischemia showed that miR-210 regulated not only vascular regeneration functions, but also inflammation. To investigate this event, doxycycline-inducible miR-210 transgenic mice (Tg-210) and anti-miR-210 LNA-oligonucleotides were used. It was found that global miR-210 expression decreased inflammatory cells density and macrophages accumulation in the ischemic tissue. To dissect the underpinning cell mechanisms, Tg-210 mice were used in bone marrow (BM) transplantation experiments and chimeric mice underwent hindlimb ischemia. MiR-210 overexpression in the ischemic tissue was sufficient to increase capillary density and tissue repair, and to reduce inflammation in the presence of Wt-BM infiltrating cells. Conversely, when Tg-210-BM cells migrated in a Wt ischemic tissue, dysfunctional angiogenesis, inflammation, and impaired tissue repair, accompanied by fibrosis were observed. The fibrotic regions were positive for α-SMA, Vimentin, and Collagen V fibrotic markers and for phospho-Smad3, highlighting the activation of TGF-β1 pathway. Identification of Tg-210 cells by in situ hybridization showed that BM-derived cells contributed directly to fibrotic areas, where macrophages co-expressing fibrotic markers were observed. Cell cultures of Tg-210 BM-derived macrophages exhibited a pro-fibrotic phenotype and were enriched with myofibroblast-like cells, which expressed canonical fibrosis markers. Interestingly, inhibitors of TGF-β type-1-receptor completely abrogated this pro-fibrotic phenotype. In conclusion, a context-dependent regulation by miR-210 of the inflammatory response was identified. miR-210 expression in infiltrating macrophages is associated to improved angiogenesis and tissue repair when the ischemic recipient tissue also expresses high levels of miR-210. Conversely, when infiltrating an ischemic tissue with mismatched miR-210 levels, macrophages expressing high miR-210 levels display a pro-fibrotic phenotype, leading to impaired tissue repair, fibrosis, and dysfunctional angiogenesis.

Project description:BackgroundThe objective of the present study was to categorize the presentation and treatment of acute limb ischemia (ALI) in young patients and compare the adverse outcomes after revascularization compared with that of older patients.MethodsAll the patients who had presented to a multi-institution healthcare system with ALI from 2016 to 2020 were identified. The presenting features, operative details, and outcomes were included in the present analysis. Patients with existing peripheral arterial disease (acute on chronic) were analyzed separately from those without (de novo thrombosis or embolus). Within these groups, younger patients (age, ≤50 years) were compared with older patients (age, >50 years). The 3-month major adverse limb event-free survival was the primary outcome.ResultsA total of 232 patients (age, 60 ± 16 years; 44% female sex, 87% white race) were included in the analysis. Of the 232 patients, 119 were in the acute on chronic cohort and 113 were in the de novo thrombosis/embolism cohort. Age did not affect the overall outcomes (P = .45) or the outcomes for the acute on chronic group (P = .17). However, in the de novo thrombosis/embolism cohort, patients aged ≤50 years had worse major adverse limb event-free survival compared with patients aged >50 years (hazard ratio, 2.47; 95% confidence interval, 1.08-5.68; P = .03) after adjustment for Rutherford class, interval from presentation to the operating room, and smoking status. In the de novo thrombosis/embolism group, the operative approach was similar across the age groups (endovascular, 12% vs 14%; open, 48% vs 41%; hybrid, 41% vs 45%; P = .78). In the younger patients, embolism was more likely from a proximal arterial source (71%). In contrast, in the older patients, the source of embolism was more often a cardiac source (86%). The rates of hypercoagulable disease were equal across the age groups (10% vs 10%; P = .95). The In-hospital mortality was 3% overall (acute on chronic, 5%; de novo, 3%).ConclusionsDespite advances in interventional options, for patients with ALI due to de novo thrombosis or embolus, younger age was associated with worse short-term limb-related outcomes.

Dataset Information

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia.

Publications

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia.

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