Sustained release of prostaglandin E1 potentiates the impaired therapeutic angiogenesis by basic fibroblast growth factor in diabetic murine hindlimb ischemia.

BACKGROUND Basic fibroblast growth factor (bFGF) is a potent mitogen; however, diabetes mellitus might impair its angiogenic property. Prostaglandin E1 (PGE1) is a potent vasodilator and improves endothelial function. Thus, PGE1 could potentiate the angiogenic properties of bFGF in patients with diabetes mellitus. METHODS AND RESULTS Streptozotocin-induced diabetic mice with unilateral hindlimb ischemia were randomly treated as follows: no treatment, 0.2 microg of PGE1, 10 microg of bFGF, and combined administration of PGE1 and bFGF. Blood perfusion was evaluated by the ratio of ischemic-to normal-limb blood perfusion. Four weeks after the treatment, the combined administration of bFGF and PGE1 increased the blood perfusion ratio as compared with single bFGF or PGE1 (77+/-10% vs 56+/-10% and 58+/-10%; p < 0.05, respectively). A histological evaluation showed that vascular density in the combined therapy was higher than single bFGF or PGE1 (418+/-59 vs 306+/-69 and 283+/-71 vessels/mm2; p < 0.01, respectively); the maturity in combined therapy was also higher than single bFGF or PGE1 (46+/-14 vs 30+/-14 and 28+/-6 vessels/mm2; p < 0.01, respectively). CONCLUSIONS PGE1 potentiated the impaired angiogenic properties of bFGF in diabetic murine hindlimb ischemia. This new strategy might contribute to more effective therapeutic angiogenesis for ischemic limb in patients with diabetes.

[1]  Y. Tabata,et al.  Combined treatment of sustained-release basic fibroblast growth factor and sarpogrelate enhances collateral blood flow effectively in rabbit hindlimb ischemia. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[2]  J. Isner,et al.  Mouse model of angiogenesis. , 1998, The American journal of pathology.

[3]  R. Lederman,et al.  Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial , 2002, The Lancet.

[4]  D. Mooney,et al.  Polymeric system for dual growth factor delivery , 2001, Nature Biotechnology.

[5]  P. Rožman,et al.  Use of platelet growth factors in treating wounds and soft-tissue injuries. , 2007, Acta dermatovenerologica Alpina, Pannonica, et Adriatica.

[6]  Y. Tabata,et al.  Toward surgical angiogenesis using slow-released basic fibroblast growth factor. , 2003, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[7]  Y. Tabata,et al.  Novel Method to Enhance Sternal Healing After Harvesting Bilateral Internal Thoracic Arteries With Use of Basic Fibroblast Growth Factor , 2000, Circulation.

[8]  B. Lévy,et al.  Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. , 2004, The American journal of pathology.

[9]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[10]  J. Vane,et al.  Intrarenal prostaglandin release attenuates the renal vasoconstrictor activity of angiotensin. , 1973, The Journal of pharmacology and experimental therapeutics.

[11]  Peter Carmeliet,et al.  VEGF gene therapy: stimulating angiogenesis or angioma-genesis? , 2000, Nature Medicine.

[12]  K. Huber,et al.  Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease. , 2002, Cardiovascular research.

[13]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[14]  G. Maurer,et al.  Prostaglandin E1 induces vascular endothelial growth factor-1 in human adult cardiac myocytes but not in human adult cardiac fibroblasts via a cAMP-dependent mechanism. , 2004, Journal of molecular and cellular cardiology.

[15]  R. Pacher,et al.  Clinical benefit of prostaglandin E1-treatment of patients with ischemic heart disease: stimulation of therapeutic angiogenesis in vital and infarcted myocardium. , 2003, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[16]  H. Okada,et al.  One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. , 1997, Advanced drug delivery reviews.

[17]  S. Epstein,et al.  Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards. , 2001, Cardiovascular research.

[18]  M. Huijberts,et al.  Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Facchiano,et al.  Sugar-induced modification of fibroblast growth factor 2 reduces its angiogenic activity in vivo. , 2002, The American journal of pathology.

[20]  Y. Tabata,et al.  Development of biologic coronary artery bypass grafting in a rabbit model: revival of a classic concept with modern biotechnology. , 2004, The Journal of thoracic and cardiovascular surgery.

[21]  Brian H Annex,et al.  Claudication of Vascular Endothelial Growth Factor 121 in Patients With Disabling Intermittent Disease : A Phase II Randomized , Double-Blind , Controlled Study of Adenoviral Delivery Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial , 2003 .

[22]  U. Ikeda,et al.  Intravenous prostaglandin E1 reduces monocyte chemoattractant protein-1 levels in peripheral arterial obstructive disease. , 2003, American heart journal.

[23]  H. Heidrich,et al.  Hemostatic and fibrinolytic effects of systemic prostaglandin E1 therapy in patients with peripheral arterial disease. , 2003, VASA. Zeitschrift fur Gefasskrankheiten.

[24]  T. Thalhammer,et al.  Angiogenesis stimulation in explanted hearts from patients pre-treated with intravenous prostaglandin E(1). , 2001, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[25]  Y. Ikada,et al.  Enhanced vascularization and tissue granulation by basic fibroblast growth factor impregnated in gelatin hydrogels , 1994 .

[26]  H. Hammes,et al.  The functional role of blood platelet components in angiogenesis , 2004, Thrombosis and Haemostasis.

[27]  B. Lévy,et al.  Molecular basis of angiopathy in diabetes mellitus. , 2005, Circulation research.

[28]  丸井 晃.  Simultaneous application of basic fibroblast growth factor and hepatocyte growth factor to enhance the blood vessels formation , 2005 .

[29]  Y. Tabata,et al.  A novel approach to therapeutic angiogenesis for patients with critical limb ischemia by sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel: an initial report of the phase I-IIa study. , 2007, Circulation journal : official journal of the Japanese Circulation Society.

[30]  W. Schaper,et al.  Involvement of the Fibroblast Growth Factor System in Adaptive and Chemokine-Induced Arteriogenesis , 2003, Circulation research.

[31]  Philippe Leboulch,et al.  Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2 , 2003, Nature Medicine.

[32]  牧野 寛史.  Increase in Peripheral Blood Flow by Intravenous Administration of Prostaglandin E1 in Patients with Peripheral Arterial Disease, Accompanied by Up-Regulation of Hepatocyte Growth Factor , 2004 .

[33]  I. Buschmann,et al.  Collateral circulation and diabetes. , 1999, Circulation.

[34]  Y Ikada,et al.  Neovascularization effect of biodegradable gelatin microspheres incorporating basic fibroblast growth factor. , 1999, Journal of biomaterials science. Polymer edition.

[35]  新井 善雄.  Combined treatment with sustained-release basic fibroblast growth factor and heparin enhances neovascularization in hypercholesterolemic mouse hindlimb ischemia , 2007 .

[36]  Takeshi Kimura,et al.  Action of aspirin on whole blood-aggregation evaluated by the screen filtration pressure method. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[37]  J. Isner,et al.  Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. , 1995, Circulation.

[38]  E. Wahlberg.  Angiogenesis and arteriogenesis in limb ischemia. , 2003, Journal of vascular surgery.

[39]  榊原 裕.  Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation , 2003 .

[40]  J. Waltenberger.  Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. , 2001, Cardiovascular research.

[41]  K Walsh,et al.  Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. , 1998, Circulation.

[42]  Hideki Ito,et al.  Genetic strain differences in platelet aggregation of laboratory mice , 2005, Thrombosis and Haemostasis.

[43]  G. King,et al.  Vascular dysfunction in diabetes mellitus , 1997, The Lancet.