Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction.
OBJECTIVE
This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate hydrogels could induce an angiogenic effect and functional improvement greater than single factors after myocardial infarction.


METHODS
Alginate hydrogels were prepared by combining high and low molecular weight alginate. Growth factor release rates were monitored over time in vitro with 125I-labelled VEGF-A(165) and PDGF-BB included in the gels. One week after myocardial infarction was induced in Fisher rats, gels with VEGF-A(165), PDGF-BB, or both were given intra-myocardially along the border of the myocardial infarction. Vessel density was analysed in hearts and cardiac function was determined by Tissue Doppler Echocardiography. In addition, the angiogenic effect of sequenced delivery was studied in vitro in aortic rings from C57B1/6 mice.


RESULTS
Alginate gels were capable of delivering VEGF-A(165) and PDGF-BB in a sustainable manner, and PDGF-BB was released more slowly than VEGF-A(165). Sequential growth factor administration led to a higher density of alpha-actin positive vessels than single factors, whereas no further increment was found in capillary density. Sequential protein delivery increased the systolic velocity-time integral and displayed a superior effect than single factors. In the aortic ring model, sequential delivery led to a higher angiogenic effect than single factor administration.


CONCLUSIONS
The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model. Sequential growth factor delivery of VEGF-A(165) and PDGF-BB induces mature vessels and improves cardiac function more than each factor singly. This may indicate clinical utility.
Hao
Xiaojin
X
Karolinska Institute at Department of Internal Medicine, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Silva
Eduardo A
EA
Månsson-Broberg
Agneta
A
Grinnemo
Karl-Henrik
KH
Siddiqui
Anwar J
AJ
Dellgren
Göran
G
Wärdell
Eva
E
Brodin
Lars Ake
LA
Mooney
David J
DJ
Sylvén
Christer
C
D000464:Alginates; D000818:Animals; D001011:Aorta / Q000187:drug effects; D000077214:Becaplermin; D004452:Echocardiography; D020723:Glucuronic Acid; D006321:Heart / Q000000981:diagnostic imaging / Q000503:physiopathology; D006603:Hexuronic Acids; D020100:Hydrogels; D066298:In Vitro Techniques; D007267:Injections; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D010982:Platelet-Derived Growth Factor / Q000627:therapeutic use*; D020574:Proto-Oncogene Proteins c-sis; D011859:Radiography; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy
D000464:Alginates; D006603:Hexuronic Acids; D020100:Hydrogels; D007457:Iodine Radioisotopes; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000077214:Becaplermin; D020723:Glucuronic Acid