Abstract
Top of pageAbstract We have previously found that the delivery of the VEGF165 cDNA into skeletal muscle using AAV vectors, not only stimulates angiogenesis and arteriogenesis, but also exerts a remarkable anti-apoptotic and pro-regenerative activity during severe ischemic injury. Based on these observations, the aim of the present study was to test whether rAAV-VEGF165 delivery into cardiac tissue, during the acute phase of myocardial infarction, exerts a protective effect on the injured myocardium and promotes long-term functional recovery. Acute infarction of the anterior LV wall was induced in twelve chronically instrumented dogs by permanent occlusion of the LAD coronary artery. Four hours after occlusion, using an echo-guided needle, we injected rAAV-VEGF (n= 6; 4x1012 viral particles per animal) or rAAV-LacZ (n=6) directly into the paradoxical segment. Hemodynamics, echocardiographic data and segmental shortening of the infarcted region were measured at baseline (pre-occlusion) and monitored repeatedly during the subsequent four weeks. Histological analysis was performed at the end of the study. LV and arterial systolic and mean pressure, LV dP/dtmax and ejection fraction were not significantly different between the two groups over time. In contrast, the indexes of contraction of the infarcted area displayed marked differences after the second week post-infarction: at four weeks, the fractional shortening was 75 |[plusmn]|18% and |[minus]|3 |[plusmn]|15% of baseline and regional shortening work was 54 |[plusmn]|15% and 0.8 |[plusmn]|15% of baseline in rAAV-VEGF165 vs. LacZ group, respectively (P<0.05). Histological analysis of the border regions between the infarcted and viable cardiac tissue showed a marked increase in the number of |[alpha]|-SMA-positive arterioles (50|[ndash]|120 |[mu]|m diameter; 68|[plusmn]|2.8 vs. 100|[plusmn]|3.8 vessels per 100x microscopic field in the LacZ and VEGF-treated animals respectively; p<0.05). In the same areas, few c-kit-positive cells (1|[ndash]|3 per field) were observed and these only in the VEGF-treated group. The histological analysis of transmural sections showed a significant improvement in myocardial viability in the VEGF group; in accordance, several troponin T-expressing cardiomyocytes displayed a clear nuclear positivity for the proliferation marker PCNA suggesting an ongoing process of active myocardial regeneration. Interestingly, in both groups of animals, the expression of the three main VEGF receptors (VEGFR-1, VEGFR-2 and NP-1) was clearly up-regulated in the border of the infarct. In particular, VEGFR-2 was found to be expressed diffusely on the surviving cardiomyocytes, reinforcing the notion of a possible direct role of VEGF in myocardial protection and/or regeneration.
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