Experimental therapeutic angiogenesis after myocardial infarction : efficacy of different angiogenic factors and delivery methods

Angiogenesis, the stimulation of vessel growth, is a promising therapy in ischemic heart disease. A wealth of evidence has shown that several growth factors can induce neovascularization in ischemic models. However, the optimal application of growth factors and delivery method requires further exploration. VEGF, the most investigated therapeutic agent was used to study angiogenic efficacy and safety. In addition, as the angiogenic process is complex with multiple growth factors involved, different combinations of growth factors and with different delivery modalities were also studied.

A rat myocardial infarction model was used to investigate angiogenic effects up to 4 weeks after delivery that was performed one week after the myocardial infarction. VEGFA165, bFGF and PDGF-BB were administered into the myocardial infarction border zone as gene in plasmid or in adenoviral vector or as protein in a slow release alginate formulation. The amount of delivered growth factor was detected as protein, mRNA or by radiolabelling. Myocardial capillary and arteriolar densities were quantitatively detected by immunohistochemistry. Apoptosis analysis was done using TUNEL staining. Left ventricular function was determined by echocardiography.

While AdhVEGF-A165 expressed VEGF-A in the myocardium to a considerably higher extent than PhVEGF-A165, both vectors increased arteriolar and capillary densities and left ventricular function to the same extent. AdhVEGF-A165 induced apoptosis and induced higher ectopic expression of VEGF-A than PhVEGF-A165. The combined growth factor delivery of PhPDGF-BB+PhbFGF or PhpDGF-BB+PhVEGF did not show any angiogenic advantage over single growth factor delivery However, when dual growth factor of PDGF-BB and VEGF-A165 were given as protein in alginate gel, more arterioles but not capillaries were observed with the dual protein transfer. Dual protein delivery increased left ventricular function better than single factor delivery.

The findings indicate that at least in the myocardial infarction model used, AdhVEGFA165 has no obvious angiogenic advantage over PhVEGF-A165 but more side effects. Combined growth factor delivery for angiogenic therapy might benefit the ischemic tissue more than single growth factor administration. However, the angiogenic effect is dependent not only on growth factors but also on delivery modality and alginate gel might be a promising utility.

List of scientific papers

I. Hao X, Mansson-Broberg A, Gustafsson T, Grinnemo KH, Blomberg P, Siddiqui AJ, Wardell E, Sylven C (2004). Angiogenic effects of dual gene transfer of bFGF and PDGF-BB after myocardial infarction. Biochem Biophys Res Commun. 315(4): 1058-63.
https://pubmed.ncbi.nlm.nih.gov/14985120

II. Hao X, Mansson-Broberg A, Blomberg P, Dellgren G, Siddiqui AJ, Grinnemo KH, Wardell E, Sylven C (2004). Angiogenic and cardiac functional effects of dual gene transfer of VEGF-A165 and PDGF-BB after myocardial infarction. Biochem Biophys Res Commun. 322(1): 292-6.
https://pubmed.ncbi.nlm.nih.gov/15313205

III. Hao X, Magnusson-Broberg A, Grinnemo KH, Dellgren G, Siddiqui AJ, Brodin LA, Sylven C (2006). Therapeutic angiogenesis. Comparison of efficacy following plasmid or adenoviral VEGF-A165 gene transfer in a rat myocardial infarction model. [Submitted]

IV. Hao X, Silva EA, Mansson-Broberg A, Dellgren G, Siddiqui AJ, Grinnemo KH, Wardell E, Brodin LA, Mooney DJ, Sylven C (2006). Therapeutic angiogenic efficacy of combination VEGF-A165 and PDGF-BB protein with alginate slow release given intramyocardially after myocardial infarction. [Manuscript]