Thromb Haemost 2008; 100(05): 871-877
DOI: 10.1160/TH07-08-0509
Endothelium and Vascular Development
Schattauer GmbH

The prostacyclin analogue iloprost increases circulating endothelial progenitor cells in patients with critical limb ischemia

Rossella Di Stefano
1   Angiology Unit, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
2   Cardiovascular Research Laboratory, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
,
Maria Chiara Barsotti
2   Cardiovascular Research Laboratory, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
,
Elio Melillo
1   Angiology Unit, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
,
Mariacarla Iorio
3   Flow Cytometry Section, Immunohaematology, Cisanello Hospital, Pisa, Italy
,
Tatiana Santoni
2   Cardiovascular Research Laboratory, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
,
Chiara Armani
2   Cardiovascular Research Laboratory, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
,
Matteo Dell’Omodarme
4   Classe di Scienze, Scuola Normale Superiore, INFN, Pisa, Italy
,
Chiara Ristori
2   Cardiovascular Research Laboratory, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
,
Raffaele De Caterina
5   Institute of Cardiology, “G. d’Annunzio” University – Chieti and C.N.R. Institute of Clinical Physiology, Pisa, Italy
,
Alberto Balbarini
1   Angiology Unit, Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy
› Author Affiliations
Further Information

Publication History

Received 19 August 2007

Accepted after major revision 12 September 2008

Publication Date:
22 November 2017 (online)

Summary

Patients with critical limb ischemia (CLI) have low levels of endothelial progenitor cells (EPC). Iloprost has been demonstrated to stimulate vascular endothelial growth factor (VEGF) and promote angiogenesis. We investigated the effects of iloprost on EPC levels in vivo in CLI patients. Twenty-three patients with stage III and IV CLI were treated with iloprost for four weeks, improving clinical and instrumental parameters. Mononuclear cells isolated from peripheral blood were cultured to obtain “early” EPC, evaluated counting adherent cells with double positivity for acetylated low-density lipoprotein uptake and Ulex Europaeus lectin at flow cytometry. These cells also co-expressed the monocyte markers CD14 and CD45.Iloprost increased EPC number in the whole patient population: pre-treatment median: 13,812/ml; range: 1,263–83,648/ml; post-treatment median: 23,739/ml; range: 3,385–99,251/ml; p=0.035, irrespective of age, sex, disease stage or atherosclerosis risk factors. In conclusion, iloprost increases EPC number in peripheral blood in vivo. Such an effect may have therapeutic relevance.

 
  • References

  • 1 Asahara T, Kawamoto A. Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol 2004; 287: C572-579.
  • 2 Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 2004; 95: 343-353.
  • 3 Kalka C, Masuda H, Takahashi T. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97: 3422-3427.
  • 4 Rehman J, Li J, Orschell CM. et al. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107: 1164-1169.
  • 5 Miraglia S, Godfrey W, Yin AH. et al. A Novel Five-Transmembrane Hematopoietic Stem Cell Antigen: Isolation, Characterization, and Molecular Cloning. Blood 1997; 90: 5013-5021.
  • 6 Case J, Mead LE, Bessler WK. et al. Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. Exp Hematol 2007; 35: 1109-1118.
  • 7 Timmermans F, Van Hauwermeiren F, De Smedt M. et al. Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arterioscler Thromb Vasc Biol 2007; 27: 1572-1579.
  • 8 Hristov M, Zernecke A, Liehn EA. et al. Regulation of endothelial progenitor cell homing after arterial injury. Thromb Haemost 2007; 98: 274-277.
  • 9 Vasa M, Fichtlscherer S, Aicher A. et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: E1-7.
  • 10 Lambiase PD, Edwards RJ, Anthopoulos P. et al. Circulating humoral factors and endothelial progenitor cells in patients with differing coronary collateral support. Circulation 2004; 109: 2986-2992.
  • 11 Landmesser U, Drexler H. The clinical significance of endothelial dysfunction. Curr Opin Cardiol 2005; 20: 547-551.
  • 12 Hill JM, Zalos G, Halcox JP. et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593-600.
  • 13 Werner N, Kosiol S, Schiegl T. et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999-1007.
  • 14 Grant SM, Goa KL. Iloprost. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peripheral vascular disease, myocardial ischaemia and extracorporeal circulation procedures. Drugs 1992; 43: 889-924.
  • 15 Hirsch AT, Haskal ZJ, Hertzer NR. et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006; 47: 1239-1312.
  • 16 Loosemore TM, Chalmers TC, Dormandy JA. A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease. Int Angiol 1994; 13: 133-142.
  • 17 Staben P, Albring M. Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost: an open study in 900 patients. Prostaglandins Leukot Essent Fatty Acids 1996; 54: 327-333.
  • 18 Meini S, De Franco V, Auteri A. et al. Short-term and long-term effects of one-week treatment with intravenous iloprost in critical limb ischemia patients (Leriche-Fontaine stage III and IV). Int Angiol 2005; 24: 64-69.
  • 19 Emanueli C, Zacheo A, Minasi A. et al. Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol 2000; 20: 2379-2385.
  • 20 Murphy JF, Steele C, Belton O. et al. Induction of cyclooxygenase-1 and –2 modulates angiogenic responses to engagement of alphavbeta3. Br J Haematol 2003; 121: 157-164.
  • 21 Smith OP, Battersby S, Sales KJ. et al. Prostacyclin receptor up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1/2 pathway. Endocrinology 2006; 147: 1697-1705.
  • 22 Murohara T, Horowitz JR, Silver M. et al. Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 1998; 97: 99-107.
  • 23 Pola R, Gaetani E, Flex A. et al. Comparative analysis of the in vivo angiogenic properties of stable prostacyclin analogs: a possible role for peroxisome proliferator-activated receptors. J Mol Cell Cardiol 2004; 36: 363-370.
  • 24 Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg 2000; 31: S1-S296.
  • 25 Melillo E, Nuti M, Pedrinelli R. et al. Is transcutaneous oxygen and carbon dioxide monitoring indispensable in short- and long-term therapeutic management of non-reconstructable lower critical limb ischemia?. Minerva Cardioangiol 2006; 54: 481-498.
  • 26 Melillo E, Ferrari M, Balbarini A. et al. Transcutaneous oxygen and carbon dioxide levels with iloprost administration in diabetic critical limb ischemia. Vasc Endovascular Surg 2006; 40: 303-311.
  • 27 Melillo E, Catapano G, Ferrari M. et al. Transcutaneous oxygen tension measurement in patients with chronic arterial obstructive disease: reliability and long-term variability of the method. Angiology 1994; 45: 469-475.
  • 28 Di Stefano R, Santoni T, Barsotti MC. et al. Different growth conditions for peripheral blood endothelial progenitors. Cardiovasc Radiat Med 2002; 03: 172-175.
  • 29 Balbarini A, Barsotti MC, Di Stefano R. et al. Circulating endothelial progenitor cells characterization, function and relationship with cardiovascular risk factors. Curr Pharm Des 2007; 13: 1699-1713.
  • 30 Criqui MH, Langer RD, Fronek A. et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381-386.
  • 31 Neilan TG, Jassal DS, Scully MF. et al. Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression. Eur Heart J 2006; 27: 1251-1256.
  • 32 Melillo E, Nuti M, Buttitta F. et al. Medical therapy in critical lower limb ischemia when immediate revascularization is not feasible. G Ital Cardiol (Rome) 2006; 07: 317-335.
  • 33 Urbich C, Dimmeler S. Endothelial progenitor cells functional characterization. Trends Cardiovasc Med 2004; 14: 318-322.
  • 34 Van Craenenbroeck EM, Conraads VM, Van Bock-staele DR. et al. Quantification of circulating endothelial progenitor cells: a methodological comparison of six flow cytometric approaches. J Immunol Methods 2008; 332: 31-40.
  • 35 Tateishi-Yuyama E, Matsubara H, Murohara T. et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; 360: 427-435.
  • 36 Vasa M, Fichtlscherer S, Adler K. et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103: 2885-2890.
  • 37 Landmesser U, Bahlmann F, Mueller M. et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111: 2356-2363.
  • 38 Bahlmann FH, De Groot K, Spandau JM. et al. Erythropoietin regulates endothelial progenitor cells. Blood 2004; 103: 921-926.
  • 39 Strehlow K, Werner N, Berweiler J. et al. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation 2003; 107: 3059-3065.
  • 40 Redondo S, Hristov M, Gumbel D. et al. Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: involvement of peroxisome proliferator-activated receptor-gamma and transforming growth factor-beta1. Thromb Haemost 2007; 97: 979-987.
  • 41 Min TQ, Zhu CJ, Xiang WX. et al. Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease. Cardiovasc Drugs Ther 2004; 18: 203-209.
  • 42 Bahlmann FH, de Groot K, Mueller O. et al. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 2005; 45: 526-529.
  • 43 Gensch C, Clever Y, Werner C. et al. Regulation of endothelial progenitor cells by prostaglandin E1 via inhibition of apoptosis. J Mol Cell Cardiol 2007; 42: 670-677.
  • 44 Atsuta H, Uchiyama T, Kanai H. et al. Effects of a stable prostacyclin analogue beraprost sodium on VEGF and PAI-1 gene expression in vascular smooth muscle cells. Int J Cardiol. 2008 Epub ahead of print.
  • 45 Hoper MM, Voelkel NF, Bates TO. et al. Prostaglandins induce vascular endothelial growth factor in a human monocytic cell line and rat lungs via cAMP. Am J Respir Cell Mol Biol 1997; 17: 748-756.
  • 46 Pueyo ME, Chen Y, D’Angelo G. et al. Regulation of vascular endothelial growth factor expression by cAMP in rat aortic smooth muscle cells. Exp Cell Res 1998; 238: 354-358.
  • 47 Park DW, Baek K, Lee JG. et al. Activation of tolllike receptor 4 modulates vascular endothelial growth factor synthesis through prostacyclin-IP signaling. Biochem Biophys Res Commun 2007; 362: 1090-1095.
  • 48 Mittag M, Beckheinrich P, Haustein UF. Systemic sclerosis-related Raynaud’s phenomenon: effects of iloprost infusion therapy on serum cytokine, growth factor and soluble adhesion molecule levels. Acta Derm Venereol 2001; 81: 294-297.
  • 49 Lenk K, Adams V, Lurz P. et al. Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia. Eur Heart J 2005; 26: 1903-1909.
  • 50 Di Stefano R, Limbruno U, Barone D. et al. Therapeutic angiogenesis of critical lower limb ischemia. Review of the literature and prospects of research on stem cells. Ital Heart J Suppl 2004; 05: 1-13.
  • 51 Fadini GP, Miorin M, Facco M. et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 2005; 45: 1449-1457.
  • 52 Fadini GP, Sartore S, Albiero M. et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 2006; 26: 2140-2146.