Dataset Information

Myeloid SOCS3 Deficiency Regulates Angiogenesis via Enhanced Apoptotic Endothelial Cell Engulfment.

ABSTRACT: Mononuclear phagocytes, such as macrophages and microglia, are key regulators of organ homeostasis including vascularization processes. Here, we investigated the role of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells as a regulator of mononuclear phagocyte function and their interaction with endothelial cells in the context of sprouting angiogenesis. As compared to SOCS3-sufficient counterparts, SOCS3-deficient microglia and macrophages displayed an increased phagocytic activity toward primary apoptotic endothelial cells, which was associated with an enhanced expression of the opsonin growth arrest-specific 6 (Gas6), a major prophagocytic molecule. Furthermore, we found that myeloid SOCS3 deficiency significantly reduced angiogenesis in an ex vivo mouse aortic ring assay, which could be reversed by the inhibition of the Gas6 receptor Mer. Together, SOCS3 in myeloid cells regulates the Gas6/Mer-dependent phagocytosis of endothelial cells, and thereby angiogenesis-related processes. Our findings provide novel insights into the complex crosstalk between mononuclear phagocytes and endothelial cells, and may therefore provide a new platform for the development of new antiangiogenic therapies.

SUBMITTER: Korovina I

PROVIDER: S-EPMC7265721 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Myeloid SOCS3 Deficiency Regulates Angiogenesis via Enhanced Apoptotic Endothelial Cell Engulfment.

Korovina Irina I Neuwirth Ales A Sprott David D Troullinaki Maria M Poitz David M DM Deussen Andreas A Klotzsche-von Ameln Anne A

Journal of innate immunity 20191001 3

Mononuclear phagocytes, such as macrophages and microglia, are key regulators of organ homeostasis including vascularization processes. Here, we investigated the role of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells as a regulator of mononuclear phagocyte function and their interaction with endothelial cells in the context of sprouting angiogenesis. As compared to SOCS3-sufficient counterparts, SOCS3-deficient microglia and macrophages displayed an increased phagocytic activity ...[more]

PMID: 31574508

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Project description:Aims: It is important to understand the mechanism that regulates post-ischemic angiogenesis and to explore a new therapeutic target for an effective improvement of revascularization in peripheral artery disease (PAD) patients. Post-ischemic angiogenesis is a highly orchestrated process, which involves vascular endothelial cells (ECs) proliferation, migration and assembly into capillaries. We found a significant reduction of S1pr2 (sphingosine 1-phosphate receptor 2) in endothelial cells after hindlimb ischemia (HLI). We thus hypothesized that EC-S1pr2 might be involved in the regulation of post-ischemic angiogenesis and blood flow recovery during peripheral arterial disease (PAD). Methods and Results: We generated both EC-specific S1pr2 loss-of-function and S1pr2 gain-of-function mice. Our study showed that EC-specific S1pr2 loss-of-function significantly enhanced post-ischemic angiogenesis and improved blood flow recovery upon femoral artery ligation, whereas the EC-specific S1pr2 gain-of-function severely hindered post-ischemic angiogenesis and reduced blood flow recovery in ischemic limbs. We next identified that S1pr2 inhibited AKT/eNOS signaling pathway, and thus inhibited EC proliferation/migration and angiogenic activity. As expected, pharmacological inhibition of S1pr2 by JTE013 improved post-ischemic angiogenesis and improved blood flow perfusion after femoral artery ligation. Moreover, we developed RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA which specifically targeted ECs and achieved an efficient silencing of S1pr2 expression in ECs in vivo. This EC-targeted strategy to dampen S1pr2 significantly enhanced post-ischemic angiogenesis and boosted blood perfusion after HLI, supplying a novel therapy target for patients with peripheral arterial disease. Conclusions: This present study demonstrates that EC-expressing S1pr2 tightly controls post-ischemic angiogenesis and blood flow perfusion recovery. This research provides a novel strategy for EC-target knockdown of S1pr2 as a new therapeutic intervention for patients with peripheral artery disease.

Dataset Information

Myeloid SOCS3 Deficiency Regulates Angiogenesis via Enhanced Apoptotic Endothelial Cell Engulfment.

Publications

Myeloid SOCS3 Deficiency Regulates Angiogenesis via Enhanced Apoptotic Endothelial Cell Engulfment.

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