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Inflammation is associated with a reduced number of pro-angiogenic Tie-2 monocytes and endothelial progenitor cells in patients with critical limb ischemia

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Abstract

Background

Inflammation is the driving force in atherosclerosis. One central strategy in the treatment for PAD is the promotion of angiogenesis. Here, pro-angiogenic Tie-2-expressing monocytes (TEM) and endothelial progenitor cells (EPC) play a crucial role. Critical limb ischemia (CLI) is characterized by a severe, chronic inflammatory response; thus, progression of the disease might be related to the deleterious effects of inflammation on pro-angiogenic cells.

Methods

Forty-five patients with intermittent claudication (IC) [three groups: Rutherford (R)-1, -2, or -3; each n = 15], 20 patients with CLI [n = 20; Rutherford 4 (15 %), 5 (40 %), and 6 (45 %)], and 20 healthy controls were included in the study. Analysis of TEM and EPC was performed from whole blood by flow cytometry. Treatment for IC patients was conservative, and CLI patients underwent surgical revascularization. Follow-up was performed after mean of 7.1 months.

Results

In comparison with healthy controls, we found increased proportions of TEM and EPC in dependence of the severity of PAD, with the highest level in patients with severe claudication (R3) (p < 0.01). In contrast, for patients with CLI, we found a significantly reduced expression of both TEM and EPC in comparison with healthy controls (p < 0.05) or IC patients (R-1, R-2, and R-3) (all p < 0.001). At follow-up, TEM and EPC in CLI patients increased significantly (both p < 0.001). Serum levels of fibrinogen and CRP were significantly increased in CLI patients (all p < 0.001), but decreased at follow-up (all p < 0.05). TEM and EPC proportions correlated inversely with levels of fibrinogen [(TEM: r = −0.266; p < 0.01) (EPC: r = −0.297; p < 0.001)], CRP (TEM: r = −0.283; p < 0.01) (EPC: r = −0.260; p < 0.01).

Conclusions

We found a strong association of diverse inflammatory markers with a reduced proportion of pro-angiogenic TEM or EPC in patients with CLI, giving rise to the speculation that a severe chronic inflammation might lead to deleterious effects on TEM and EPC, possibly interfering with angiogenesis, thus promoting an aggravation of the disease.

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Acknowledgments

This paper contains in part data reported in the medical thesis of Jennifer Rubrech, Amelie Trumpp, and Philip Geissler. The authors like to thank Ursel Petrat, Sabine Wolk, and Andrea Drescher for excellent technical support.

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Authors and Affiliations

  1. Department of Internal Medicine II, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Jörn F. Dopheide, Philipp Geissler, Jennifer Rubrech, Amelie Trumpp, Karsten Bock, Thomas Münzel & Christine Espinola-Klein

  2. Department of Internal Medicine I, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany

    Geraldine C. Zeller

  3. Department of Internal Medicine III, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany

    Markus P. Radsak

  4. Institute for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany

    Markus P. Radsak

  5. Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center, Johannes-Gutenberg University, Mainz, Germany

    Bernhard Dorweiler & Friedrich Dünschede

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  1. Jörn F. Dopheide
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  2. Philipp Geissler
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Correspondence to Jörn F. Dopheide.

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Dopheide, J.F., Geissler, P., Rubrech, J. et al. Inflammation is associated with a reduced number of pro-angiogenic Tie-2 monocytes and endothelial progenitor cells in patients with critical limb ischemia. Angiogenesis 19, 67–78 (2016). https://doi.org/10.1007/s10456-015-9489-y

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