The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides.

For successful treatment of myocardial infarction (MI), it is important to prevent cardiac fibrosis and maintain cardiac function by protecting cardiomyocytes and inducing angiogenesis. To establish functional and stable vessels, various growth factors, ones stimulating both endothelial cells (EC) and vascular smooth muscle cells (VSMC), are required. Self-assembling peptides form fibers (<10 nm) and provide 3-dimensional microenvironments that can recruit EC and VSMC to promote vascularization and long-term delivery of growth factors. Here we demonstrate myocardial protection of infarcted heart using dual growth factor delivery with self-assembling peptides. After coronary artery ligation in rats, growth factors (PDGF-BB and FGF-2) with self-assembling peptides were injected. There were 6 rats in each group. Hearts were harvested at 4 and 8 weeks for functional and histological analysis. Infarct size and cardiomyocyte apoptosis in dual growth factors along with self-assembling peptides group were dramatically reduced compared to sham. The capillary and arterial density of this group recovered with angiogenic synergism and cardiac functions had almost recovered. In conclusion, dual growth factors along with self-assembling peptides lead to myocardial protection, stable vessel formation, and improvement in cardiac function.

[1]  K. Sun,et al.  Regeneration of ischemic heart using hyaluronic acid-based injectable hydrogel. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[2]  Thomas Eschenhagen,et al.  Engineering Myocardial Tissue , 2005, Circulation research.

[3]  R O Bonow,et al.  Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary. , 2000, Circulation.

[4]  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.

[5]  H. Blau,et al.  Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. , 2004, The Journal of clinical investigation.

[6]  Nobuyuki Itoh,et al.  Fibroblast growth factors , 2001, Genome Biology.

[7]  P. Anversa Myocyte death in the pathological heart. , 2000, Circulation research.

[8]  Randall J Lee,et al.  Biomaterials for the treatment of myocardial infarction. , 2006, Journal of the American College of Cardiology.

[9]  Shuguang Zhang,et al.  Fabrication of molecular materials using peptide construction motifs. , 2004, Trends in biotechnology.

[10]  Yihai Cao,et al.  R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways , 2008, Journal of Molecular Medicine.

[11]  G. Prestwich,et al.  Stimulation of in vivo angiogenesis by in situ crosslinked, dual growth factor-loaded, glycosaminoglycan hydrogels. , 2010, Biomaterials.

[12]  Peter Carmeliet,et al.  Growing better blood vessels , 2001, Nature Biotechnology.

[13]  Matthias P Lutolf,et al.  Biopolymeric delivery matrices for angiogenic growth factors. , 2003, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[14]  Carlos E Semino,et al.  The effect of functionalized self-assembling peptide scaffolds on human aortic endothelial cell function. , 2005, Biomaterials.

[15]  S. Silver,et al.  Heart Failure , 1937, The New England journal of medicine.

[16]  Yihai Cao,et al.  Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs , 2007, Proceedings of the National Academy of Sciences.

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

[18]  A R Boccaccini,et al.  Myocardial tissue engineering: a review , 2007, Journal of tissue engineering and regenerative medicine.

[19]  Fabrizio Gelain,et al.  Designer self-assembling peptide scaffolds for 3-d tissue cell cultures and regenerative medicine. , 2007, Macromolecular bioscience.

[20]  B R Johansson,et al.  Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. , 1997, Science.

[21]  M. Simons,et al.  Growth factor-induced therapeutic angiogenesis in the heart: protein therapy. , 2005, Cardiovascular research.

[22]  Michael Simons,et al.  Role of Angiogenesis in Cardiovascular Disease : a Critical Appraisal , 2022 .

[23]  M. Simons Angiogenesis: where do we stand now? , 2005, Circulation.

[24]  David J Mooney,et al.  Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction. , 2007, Cardiovascular research.

[25]  Yihai Cao,et al.  Differential roles of PDGFR‐α and PDGFR‐β in angiogenesis and vessel stability , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  E. Kardami,et al.  Biological activities of fibroblast growth factor-2 in the adult myocardium. , 2003, Cardiovascular research.

[27]  Shuguang Zhang Fabrication of novel biomaterials through molecular self-assembly , 2003, Nature Biotechnology.

[28]  Richard T. Lee,et al.  Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. , 2005, The Journal of clinical investigation.

[29]  Richard T. Lee,et al.  Custom Design of the Cardiac Microenvironment With Biomaterials , 2005, Circulation research.

[30]  G. Semenza,et al.  Vasculogenesis, angiogenesis, and arteriogenesis: Mechanisms of blood vessel formation and remodeling , 2007, Journal of cellular biochemistry.

[31]  Yihai Cao,et al.  Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. , 2007, The Journal of clinical investigation.

[32]  Richard T. Lee,et al.  Self-assembling short oligopeptides and the promotion of angiogenesis. , 2005, Biomaterials.

[33]  M. Kawasuji,et al.  Effects of intramyocardial administration of slow-release basic fibroblast growth factor on angiogenesis and ventricular remodeling in a rat infarct model. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[34]  Masashi Komeda,et al.  Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model , 2003, Heart and Vessels.

[35]  Fabrizio Gelain,et al.  Biological Designer Self-Assembling Peptide Nanofiber Scaffolds Significantly Enhance Osteoblast Proliferation, Differentiation and 3-D Migration , 2007, PloS one.

[36]  Richard T. Lee,et al.  Injectable Self-Assembling Peptide Nanofibers Create Intramyocardial Microenvironments for Endothelial Cells , 2005, Circulation.

[37]  G. Schneider,et al.  Nano neuro knitting: peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Richard T. Lee,et al.  Local delivery of proteins and the use of self-assembling peptides. , 2007, Drug discovery today.

[39]  Richard T. Lee,et al.  Local Controlled Intramyocardial Delivery of Platelet-Derived Growth Factor Improves Postinfarction Ventricular Function Without Pulmonary Toxicity , 2006, Circulation.

[40]  E. Feigl,et al.  Fibroblast growth factor-2 regulates myocardial infarct repair: effects on cell proliferation, scar contraction, and ventricular function. , 2007, The American journal of pathology.

[41]  Robert J Fisher,et al.  Dual growth factor-induced angiogenesis in vivo using hyaluronan hydrogel implants. , 2006, Biomaterials.

[42]  W. Aird,et al.  PDGF mediates cardiac microvascular communication. , 1998, The Journal of clinical investigation.