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(Circulation. 2004;109:1029-1035.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Adenoviral Catheter-Mediated Intramyocardial Gene Transfer Using the Mature Form of Vascular Endothelial Growth Factor-D Induces Transmural Angiogenesis in Porcine Heart

Juha Rutanen, MD^*; Tuomas T. Rissanen, MD, PhD^*; Johanna E. Markkanen, MD; Marcin Gruchala, MD; Päivi Silvennoinen, MD; Antti Kivelä, MD; Antti Hedman, MD, PhD; Marja Hedman, MD, PhD; Tommi Heikura, MSc; Maija-Riitta Ordén, MD, PhD; Steven A. Stacker, PhD; Marc G. Achen, PhD; Juha Hartikainen, MD, PhD; Seppo Ylä-Herttuala, MD, PhD

From the Department of Molecular Medicine, A.I. Virtanen Institute, Kuopio University, Finland (J.R., T.T.R., J.E.M., M.G., P.S., T.H., M.-R.O., S.Y.-H.); the Departments of Medicine (A.K., A.H., M.H., J.H., S.Y.-H.) and Obstetrics and Gynecology (M.-R.O.) and the Gene Therapy Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland; and the Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia (S.A.S., M.G.A.).

Correspondence to Seppo Ylä-Herttuala, MD, PhD, FESC, A. I. Virtanen Institute, Kuopio University, PO Box 1627, FIN-70211 Kuopio, Finland. E-mail seppo.ylaherttuala{at}uku.fi

Received May 13, 2003; de novo received August 28, 2003; revision received October 28, 2003; accepted October 31, 2003.

Background— It is unclear what is the most efficient vector and growth factor for induction of therapeutic vascular growth in the heart. Furthermore, the histological nature of angiogenesis and potential side effects caused by different vascular endothelial growth factors (VEGFs) in myocardium have not been documented.

Methods and Results— Adenoviruses (Ad) at 2 doses (2x10¹¹ and 2x10¹² viral particles) or naked plasmids (1 mg) encoding LacZ control, VEGF-A₁₆₅, or the mature, soluble form of VEGF-D (VEGF-D^NC) were injected intramyocardially with the NOGA catheter system into domestic pigs. AdVEGF-D^NC gene transfer (GT) induced a dose-dependent myocardial protein production, as measured by ELISA, resulting in an efficient angiogenic effect 6 days after the injections. Also, AdVEGF-A₁₆₅ produced high gene transfer efficacy, as demonstrated with immunohistochemistry, leading to prominent angiogenesis effects. Despite the catheter-mediated approach, angiogenesis induced by both AdVEGFs was transmural, with maximal effects in the epicardium. Histologically, strongly enlarged -smooth muscle actin–positive microvessels involving abundant cell proliferation were found in the transduced regions, whereas microvessel density did not change. Myocardial contrast echocardiography and microspheres showed marked increases in perfusion in the transduced areas. VEGF-D^NC but not matrix-bound VEGF-A₁₆₅ was detected in plasma after adenoviral GT. A modified Miles assay demonstrated myocardial edema resulting in pericardial effusion with the higher AdVEGF doses. All effects returned to baseline by 3 weeks. Naked plasmid–mediated GT did not induce detectable protein production or vascular effects.

Conclusions— Like AdVEGF-A₁₆₅, AdVEGF-D^NC GT using the NOGA system produces efficient transmural angiogenesis and increases myocardial perfusion. AdVEGF-D^NC could be useful for the induction of therapeutic vascular growth in the heart.

Key Words: angiogenesis • echocardiography • gene therapy • perfusion • regional blood flow

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