Role of Serum Levels of Angiogenic Cytokines in Assessment of Angiogenesis after Stem Cell Therapy of Diabetic Patients with Critical Limb Ischemia

Abstract

The release of proangiogenic cytokines into the circulation after stem cell (SC) therapy and compensatory increase of angiogenesis inhibitors may reflect local vasculogenesis but also can increase the risk of side effects. The aim of our study was to evaluate serum levels of angiogenic cytokines with regard to the assessment of local and systemic vasculogenesis in diabetic patients with no-option critical limb ischemia (NO-CLI). Twentyfive diabetic patients with NO-CLI treated with SCs isolated from bone marrow or stimulated peripheral blood were included in the study. Serum levels of proangiogenic cytokines (VEGF, bFGF, Ang-1, PDGF-AA, and PDGF-BB) and an antiangiogenic cytokine (endostatin) were assessed 6 months after cell treatment, compared to baseline values, and correlated with the number of injected CD34 + cells. The clinical effect of SC therapy (assessed by changes in TcPO 2 ) and potential systemic vasculogenesis (assessed by eye fundus examination) were evaluated after 6 months. Serum levels of angiogenic inhibitor endostatin increased significantly after 1 and 3 months (p = 0.0003), but no significant increase in serum levels of proangiogenic cytokines was observed. A significant correlation between number of injected CD34 + cells and serum levels of endostatin was observed (r = 0.41, p < 0.05); however, proangiogenic cytokines did not correlate with CD34 + cells. No correlation between increase in TcPO 2 after treatment and serum levels of any of the angiogenic cytokines were seen, and no signs of systemic vasculogenesis in the retina were observed after 6 months. Despite the significant increase in the levels of the angiogenic inhibitor endostatin following SC treatment, there was no risk of systemic vasculogenesis after SC therapy as documented by serum levels of proangiogenic cytokines or changes in the retina.

Comparison of the effect of stem cell therapy and percutaneous transluminal angioplasty on diabetic foot disease in patients with critical limb ischemia

“…We also did not observe an increase in serum levels of pro-angiogenic cytokines during 6 months of followup and no changes in the retina after autologous SCT in terms of induction of systemic angiogenesis [21].…”

Difference in Serum Endostatin Levels in Diabetic Patients with Critical Limb Ischemia Treated by Autologous Cell Therapy or Percutaneous Transluminal Angioplasty

“…The release of pro- and anti-angiogenic factors is a possible modulator of vasculogenesis 19 . The most important pro-angiogenic factors include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) 20 , angiopoietin-1, platelet-derived growth factors (PDGF-AA, PDGF-BB), or hypoxia-inducible factor (HIF-1α) 21 , whereas the main anti-angiogenic factors are represented by endostatin, angiostatin, arresten, canstatin, tumstatin, or thrombospondins 22 .…”

“…Previously, we assessed the serum levels of pro-angiogenic factors as markers of systemic side effects of ACT 19 . We observed no significant increase in the serum levels of pro-angiogenic factors and found no signs of distal systemic vasculogenesis on fundoscopic examination of the eye.…”

Serum C-peptide level correlates with the course of muscle tissue healing in the rabbit model of critical limb ischemia

“…Dubsky et al assessed the levels of proangiogenic (VEGF, bFGF, Ang-1, and PDGF) and antiangiogenic (endostatin) factor levels in the venous blood of diabetic patients undergoing bone marrow or peripheral blood stem cell transplantation. No significant change in the serum levels of proangiogenic cytokines was observed 6 months after transplantation 32 . Based on our results as well as those of other authors, it seems difficult to monitor the tissue healing process based on systemic cytokine levels.…”