Ischaemic tissue released microvesicles induce monocyte reprogramming and increase tissue repair by a tissue factor-dependent mechanism
Por:
Arderiu, G, Pena, E, Badimon, L
Publicada:
27 jul 2022
Ahead of Print:
1 ago 2021
Resumen:
Aims Despite increasing evidence that monocytes may acquire endothelial features, it remains unclear how monocytes participate in angiogenesis after ischaemic damage. We investigated whether ischaemic cells can release microvesicles (MVs) and promote neovascularization in a model of peripheral artery disease (PAD). Methods and results To model PAD, we used an in vivo experimental model of hind-limb ischaemia (HLI) in mice. MVs were isolated from the ischaemic muscle and from peripheral blood at different times after unilateral femoral artery ligation. MVs were phenotypically characterized to identify cell origin. HLI in mice induced the release of MVs with a much higher content of tissue factor (TF) than non-HLI control mice both in the MVs isolated from the affected limb muscle area and from blood. MVs were mainly released from endothelial cells (ECs) and induced Mo differentiation to endothelial cell-like (ECL) cells. Differentiation to ECL cells encompassed highly strict hierarchical transcription factor activation, initiated by ETS1 activation. MVs secreted by microvascular ECs over-expressing TF (upTF-EMVs), were injected in the ischaemic hind-limb in parallel with control EMVs (from random siRNA-treated cells) or EMVs released by silenced TF ECs. In animals treated with upTF-EMVs in the ischaemic zone, there was a highly significant increase in functional new vessels formation (seen by magnetic resonance angiography), a concomitant increase in the pool of circulating Ly6C(low) Mo expressing vascular EC markers, and a significantly higher number of Mo/macrophages surrounding and integrating the newly formed collaterals. Conclusion Ischaemia-activated ECs release EMVs rich in TF that induce monocyte differentiation into ECL cells and the formation of new vessels in the ischaemic zone. TF by this mechanism of formation of new blood microvessels can contribute to ischaemic tissue repair.
Filiaciones:
Arderiu, G:
Hosp Santa Creu & Sant Pau, Cardiovasc Program ICCC, Inst Recerca, IIB St Pau, Carrer St Antoni Maria Claret 167, Barcelona 08025, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
Pena, E:
Hosp Santa Creu & Sant Pau, Cardiovasc Program ICCC, Inst Recerca, IIB St Pau, Carrer St Antoni Maria Claret 167, Barcelona 08025, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
Badimon, L:
Hosp Santa Creu & Sant Pau, Cardiovasc Program ICCC, Inst Recerca, IIB St Pau, Carrer St Antoni Maria Claret 167, Barcelona 08025, Spain
Inst Carlos III, Ciber CV, Madrid, Spain
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