Adenoviral VEGF-B186R127S gene transfer induces angiogenesis and improves perfusion in ischemic heart
Henna Korpela,
Olli-Pekka Hätinen,
Tiina Nieminen,
Rahul Mallick,
Pyry Toivanen,
Jonna Airaksinen,
Kaisa Valli,
Mikko Hakulinen,
Pekka Poutiainen,
Jussi Nurro,
Seppo Ylä-Herttuala
Affiliations
Henna Korpela
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Olli-Pekka Hätinen
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Tiina Nieminen
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Kuopio Center for Gene and Cell Therapy, Kuopio, Finland
Rahul Mallick
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Pyry Toivanen
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Jonna Airaksinen
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Kaisa Valli
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Mikko Hakulinen
Kuopio University Hospital, Kuopio, Finland
Pekka Poutiainen
Kuopio University Hospital, Kuopio, Finland
Jussi Nurro
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Seppo Ylä-Herttuala
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland; Corresponding author
Summary: Vascular endothelial growth factor B (VEGF-B) is an interesting therapeutic candidate for coronary artery disease. However, it can also cause ventricular arrhythmias, potentially preventing its use in clinics. We cloned VEGF-B isoforms with different receptor binding profiles to clarify the roles of VEGFR-1 and Nrp-1 in angiogenesis and to see if angiogenic properties can be maintained while avoiding side effects. VEGF-B constructs were studied in vivo using adenovirus (Ad)-mediated intramyocardial gene transfers into the normoxic and ischemic porcine heart (n = 51). It was found that the unprocessed isoform VEGF-B186R127S is as efficient angiogenic growth factor as the native VEGF-B186 in normoxic and ischemic heart. In addition, AdVEGF-B186R127S increased myocardial perfusion reserve by 22% in ischemic heart without any side effects. AdVEGF-B127 (VEGFR-1 and Nrp-1 ligand) and AdVEGF-B109 (VEGFR-1 ligand) did not induce angiogenesis. Thus, VEGF-B186 is angiogenic only before its proteolytic processing to VEGF-B127. Only the VEGF-B186 C-terminal fragment was associated with arrhythmias.
