Ischaemic tissue released microvesicles induce monocyte reprogramming and increase tissue repair by a tissue factor-dependent mechanism

Autor: Esther Peña, Lina Badimon, Gemma Arderiu
Rok vydání: 2022
Předmět:
Zdroj: CARDIOVASCULAR RESEARCH
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 0008-6363
Popis: Aims Despite increasing evidence that monocytes may acquire endothelial features, it remains unclear how monocytes participate in angiogenesis after ischemic damage. We investigated whether ischemic cells can release microvesicles (MVs) and promote neovascularisation in a model of peripheral artery disease (PAD). Methods and results To model PAD we used an in vivo experimental model of hind limb ischemia (HLI) in mice. MVs were isolated from the ischemic 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 hierarchycal transcription factor activation, initiated by ETS1 activation. MVs secreted by microvascular ECs overexpressing TF (upTF-EMVs), were injected in the ischemic hind limb in parallel with control EMVs (from random siRNA-treated cells) or EMVs released by silenced TF endothelial cells (siTF-EMVs). In animals treated with upTF-EMVs in the ischemic 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 Ly6Clow Mo expressing vascular endothelial cell markers, and a significantly higher number of Mo/Macrophages surrounding and integrating the newly formed collaterals. Conclusion Ischemia-activated ECs release EMVs rich in TF that induce monocyte differentiation into ECL cells and the formation of new vessels in the ischemic zone. TF by this mechanism of formation of new blood microvessels can contribute to ischemic tissue repair. Translational perspective Neovascularization is the cornerstone of limb preservation in peripheral artery disease. Neovessel formation occurring during postnatal development is usually connected with inflammation. Advanced studies in the field of vascular biology have reported that monocytes can acquire endothelial features under angiogenic stimulation. We report that after ischemia affected endothelial cells release microvesicles rich in tissue factor that act as endogenous triggers by interacting with monocytes in an autocrine fashion, coaxing the cells to differentiate into functional endothelial cells. These differentiated cells have the ability to increase blood flow into ischemic tissue. The present study depicts a new concept in the mechanisms governing vessel formation in ischemic tissue.
Databáze: OpenAIRE
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