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

doi:10.1016/j.isci.2021.103533

Adenoviral VEGF-B186R127S gene transfer induces angiogenesis and improves perfusion in ischemic heart

iScience. 2021 Nov 27;24(12):103533. doi: 10.1016/j.isci.2021.103533. eCollection 2021 Dec 17.

Authors

Affiliations

¹ A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
² Kuopio Center for Gene and Cell Therapy, Kuopio, Finland.
³ Kuopio University Hospital, Kuopio, Finland.
⁴ Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.

Abstract

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.

Keywords: Biochemistry; Cellular therapy; Molecular biology.