P252	Structural pathways for permeability in the heart after adenoviral intramyocardial gene transfer of VEGF-D.
1F.Verheyen, 2J.Markkanen, 2S.Ylä-Herttuala, 1J.Waltenberger, the participants in "Therapeutic strategies using VEGF"
1Univ. Maastricht, Dept. Vasc. & Mol. Biol., CARIM, Maastricht, NL; 2Univ. Kuopio, Dept. Biotechnol. & Mol. Med., A.I. Virtanen Institute, Kuopio, FI.

Fons Verheyen1, Johanna Markkanen2, Seppo Ylä-Herttuala2, Johannes Waltenberger1. 1Dept. Vasc. & Mol. Biol., CARIM, Univ. Maastricht, The Netherlands and 2Dept. Biotechnol. & Mol. Med., A.I. Virtanen Institute, Univ. Kuopio, Finland. Therapeutic angiogenesis induced by vascular growth factors may be a novel treatment option for ischemic heart disease. Adenoviral gene transfer of the mature, soluble form of VEGF-D (AdVEGF-DΔNΔC) in the porcine myocardium has been described to induce significant angiogenesis resulting in increased tissue perfusion (Rutanen et al., Circulation. 2004; 109: 1029-1035). However, an increased vascular permeability was seen with high doses of viral particles. To obtain more information about the structural pathways for permeability induced by gene transfer, a light and electron microscopical evaluation was performed at 6 days after transfer. Light microscopy revealed obvious edema formation in the transduced area around enlarged angiogenic preexisting microvessels with loss of cohesion of myocardial cells. Some extravasation of mononuclear white blood cells and erythrocytes could be observed as well. At the electron microscopical level, the interendothelial junctional complex of many angiogenic microvessels consisted of 1-4 adherens junctions per complex which was different from the dual complex (adherens + tight junction) present in normal capillaries in the non-transduced control area. In addition to the junctional change, fenestrated capillaries were frequently encountered in the transduced but not in the non-transduced area. Furthermore, erythrocytes were seen to extravasate through gaps created by apoptotic degeneration of single endothelial cells in the enlarged microvessels. Taken together, at least three routes of extravasation can be considered for VEGF-DΔNΔC-induced permeability increase in the angiogenic capillaries. Further studies are needed to determine the contribution of each of these routes to the edema formation observed and may provide novel guidance related to potential toxicity and efficiency of pro-angiogenic gene therapy.

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