Abstract
Vascular endothelial growth factor (VEGF), an independent mitogen, has been reported to induce angiogenesis and thus attenuates the damage induced by myocardial infarction (MI). VEGF165 is the most abundant and predominant isoform of VEGF. This study investigates whether this effect could be strengthened by local intramyocardial injection of VEGF165 along with a novel biodegradable Dex-PCL-HEMA/PNIPAAm hydrogel and ascertains its possible mechanism of action. Rat models of myocardial infarction were induced by coronary artery ligation. Phosphate-buffered saline (PBS group), Dex-PCL-HEMA/PNIPAAm hydrogel (Gel group), phosphate-buffered saline containing VEGF165 (VP group), and hydrogel containing VEGF165 (VPG group) were injected into a peri-infarcted area of cardiac tissue immediately after myocardial infarction, respectively. The sham group was thoracic but without myocardial infarction. The injection of VEGF165 along with a hydrogel induced angiogenesis, reduced collagen content and MI area, inhibited cell apoptosis, increased the level of VEGF165 protein and the expression of flk-1 and flt-1, and improved cardiac function compared with the injection of either alone after MI in rats. The results suggest that injection of VEGF165 along with a hydrogel acquires more cardioprotective effects than either alone in rat with MI by sustained release of VEGF165, then may enhance the feedback between VEGF and its receptors flk-1 and flt-1.
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References
Zhang BH, Guo CX, Wang HX, Lu LQ, Wang YJ, Zhang LK, Du FH, Zeng XJ (2014) Cardioprotective effects of adipokine apelin on myocardial infarction. Heart Vessels 29(5):679–689
Sun Y, Weber KT (2000) Infarct scar: a dynamic tissue. Cardiovasc Res 46(2):250–256
Colucci WS (1997) Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 80(11A):15L–25L
Mann DL (1999) Mechanisms and models in heart failure: a combinatorial approach. Circulation 100(9):999–1008
Jiang XJ, Wang T, Li XY, Wu DQ, Zheng ZB, Zhang JF, Chen JL, Peng B, Jiang H, Huang C, Zhang XZ (2009) Injection of a novel synthetic hydrogel preserves left ventricle function after myocardial infarction. J Biomed Mater Res A 90(2):472–477
Cabiati M, Martino A, Mattii L, Caselli C, Prescimone T, Lionetti V, Morales MA, Del Ry S (2014) Adenosine receptor expression in an experimental animal model of myocardial infarction with preserved left ventricular ejection fraction. Heart Vessels 29(4):513–519
Tamura K, Nakajima H, Rakue H, Sasame A, Naito Y, Nagai Y, Ibukiyama C (1999) Elevated circulating levels of basic fibroblast growth factor and vascular endothelial growth factor in patients with acute myocardial infarction. Jpn Circ J 63(5):357–361
Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E (1994) Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc Res 28(8):1176–1179
Haynesworth SE, Baber MA, Caplan AI (1996) Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 166(3):585–592
Yin R, Feng J, Chen D, Wu H (2000) Serum levels of vascular endothelial growth factor in patients with angina pectoris and acute myocardial infarction. Chin Med Sci J 15(4):205–209
Yin R, Feng J, Yao Z (2000) Dynamic changes of serum vascular endothelial growth factor levels in a rat myocardial infarction model. Chin Med Sci J 15(3):154–156
Soeki T, Tamura Y, Shinohara H, Tanaka H, Bando K, Fukuda N (2000) Role of circulating vascular endothelial growth factor and hepatocyte growth factor in patients with coronary artery disease. Heart Vessels 15(3):105–111
Kumagai M, Marui A, Tabata Y, Takeda T, Yamamoto M, Yonezawa A, Tanaka S, Yanagi S, Ito-Ihara T, Ikeda T, Murayama T, Teramukai S, Katsura T, Matsubara K, Kawakami K, Yokode M, Shimizu A, Sakata R (2015) Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia. Heart Vessels. doi:10.1007/s00380-015-0677-x
Yuan QY, Zhu ZW, Wang Z, Wang XM, Li XS, Huang J, Si LY (2012) A novel method of augmenting gene expression and angiogenesis in the normal and ischemic canine myocardium. Heart Vessels 27(3):316–326
Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM (1994) Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 93(2):662–670
Mack CA, Patel SR, Schwarz EA, Zanzonico P, Hahn RT, Ilercil A, Devereux RB, Goldsmith SJ, Christian TF, Sanborn TA, Kovesdi I, Hackett N, Isom OW, Crystal RG, Rosengart TK (1998) Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J Thorac Cardiovasc Surg 115(1):168–176 (discussion 176–167)
Yla-Herttuala S, Martin JF (2000) Cardiovascular gene therapy. Lancet 355(9199):213–222
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676
Ferrara N, Houck K, Jakeman L, Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13(1):18–32
Post MJ, Laham R, Sellke FW, Simons M (2001) Therapeutic angiogenesis in cardiology using protein formulations. Cardiovasc Res 49(3):522–531
Hughes GC, Biswas SS, Yin B, Coleman RE, DeGrado TR, Landolfo CK, Lowe JE, Annex BH, Landolfo KP (2004) Therapeutic angiogenesis in chronically ischemic porcine myocardium: comparative effects of bFGF and VEGF. Ann Thorac Surg 77(3):812–818
Davis ME, Hsieh PC, Takahashi T, Song Q, Zhang S, Kamm RD, Grodzinsky AJ, Anversa P, Lee RT (2006) Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc Natl Acad Sci USA 103(21):8155–8160
Salimath AS, Phelps EA, Boopathy AV, Che PL, Brown M, Garcia AJ, Davis ME (2012) Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats. PLoS One 7(11):e50980
Engel FB, Hsieh PC, Lee RT, Keating MT (2006) FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci USA 103(42):15546–15551
Epstein SE, Kornowski R, Fuchs S, Dvorak HF (2001) Angiogenesis therapy: amidst the hype, the neglected potential for serious side effects. Circulation 104(1):115–119
He YY, Wen Y, Zheng XX (2013) Jiang XJ (2013) Intramyocardial delivery of HMGB1 by a novel thermosensitive hydrogel attenuates cardiac remodeling and improves cardiac function after myocardial infarction. J Cardiovasc Pharmacol 61(4):283–290
Wan WG, Jiang XJ, Li XY, Zhang C, Yi X, Ren S, Zhang XZ (2014) Enhanced cardioprotective effects mediated by plasmid containing the short-hairpin RNA of angiotensin converting enzyme with a biodegradable hydrogel after myocardial infarction. J Biomed Mater Res A 102(10):3452–3458
Christman KL, Lee RJ (2006) Biomaterials for the treatment of myocardial infarction. J Am Coll Cardiol 48(5):907–913
Dai W, Wold LE, Dow JS, Kloner RA (2005) Thickening of the infarcted wall by collagen injection improves left ventricular function in rats: a novel approach to preserve cardiac function after myocardial infarction. J Am Coll Cardiol (JACC) 46(4):714–719
Hao X, Silva EA, Mansson-Broberg A, Grinnemo KH, Siddiqui AJ, Dellgren G, Wardell E, Brodin LA, Mooney DJ, Sylven C (2007) Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction. Cardiovasc Res 75(1):178–185
Leor J, Amsalem Y, Cohen S (2005) Cells, scaffolds, and molecules for myocardial tissue engineering. Pharmacol Therapeut 105(2):151–163
Landa N, Miller L, Feinberg MS, Holbova R, Shachar M, Freeman I, Cohen S, Leor J (2008) Effect of injectable alginate implant on cardiac remodeling and function after recent and old infarcts in rat. Circulation 117(11):1388–1396
Kofidis T, Lebl DR, Martinez EC, Hoyt G, Tanaka M, Robbins RC (2005) Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury. Circulation 112(9 Suppl):I173–I177
Davis ME, Motion JP, Narmoneva DA, Takahashi T, Hakuno D, Kamm RD, Zhang S, Lee RT (2005) Injectable self-assembling peptide nanofibers create intramyocardial microenvironments for endothelial cells. Circulation 111(4):442–450
Luo D, Saltzman WM (2000) Synthetic DNA delivery systems. Nat Biotechnol 18(1):33–37
Wu DQ, Qiu F, Wang T, Jiang XJ, Zhang XZ, Zhuo RX (2009) Toward the development of partially biodegradable and injectable thermoresponsive hydrogels for potential biomedical applications. ACS Appl Mater Interfaces 1(2):319–327
Wang T, Wu DQ, Jiang XJ, Zhang XZ, Li XY, Zhang JF, Zheng ZB, Zhuo R, Jiang H, Huang C (2009) Novel thermosensitive hydrogel injection inhibits post-infarct ventricle remodelling. Eur J Heart Fail 11(1):14–19
Chen L, Mupo A, Huynh T, Cioffi S, Woods M, Jin C, McKeehan W, Thompson-Snipes L, Baldini A, Illingworth E (2010) Tbx1 regulates Vegfr3 and is required for lymphatic vessel development. J Cell Biol 189(3):417–424
Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M (1996) VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270(5 Pt 2):H1803–H1811
Infanger M, Faramarzi S, Grosse J, Kurth E, Ulbrich C, Bauer J, Wehland M, Kreutz R, Kossmehl P, Paul M, Grimm D (2007) Expression of vascular endothelial growth factor and receptor tyrosine kinases in cardiac ischemia/reperfusion injury. Cardiovasc Pathol 16(5):291–299
Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269(43):26988–26995
Roskoski R Jr (2008) VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun 375(3):287–291
Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18(1):4–25
Shibuya M (2006) Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 39(5):469–478
Yang XH, Man XY, Cai SQ, Yao YG, Bu ZY, Zheng M (2006) Expression of VEGFR-2 on HaCaT cells is regulated by VEGF and plays an active role in mediating VEGF induced effects. Biochem Biophys Res Commun 349(1):31–38
Hashimoto E, Ogita T, Nakaoka T, Matsuoka R, Takao A, Kira Y (1994) Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. The Am J Physiol 267(5 Pt 2):H1948–H1954
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The authors thank the contract grant sponsors National Nature Science Foundation of China (contract grant number: 81170307), National Key Basic Research Program of China (contract grant number: 2005CB623903) and The Fundamental Research Funds for the Central Universities;contract grant number: 2042014kf0130.
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Zhu, H., Jiang, X., Li, X. et al. Intramyocardial delivery of VEGF165 via a novel biodegradable hydrogel induces angiogenesis and improves cardiac function after rat myocardial infarction. Heart Vessels 31, 963–975 (2016). https://doi.org/10.1007/s00380-015-0710-0
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DOI: https://doi.org/10.1007/s00380-015-0710-0