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Figure 3 Adenoviral AdVEGF-A₁₆₅ Gene Transfer Promotes Efficient Angiogenesis and an Acute Increase In Tissue Perfusion

(A and F) CD31 immunostainings of normal rabbit skeletal muscle transduced intramuscularly with AdLacZ or adenoviral vascular endothelial growth factor (AdVEGF)-A at 6 days earlier demonstrate abundant enlargement of preexisting capillaries after AdVEGF-A gene transfer. (Insets) CD31 (blue) + BrDU (brown) double stainings show that capillary enlargement with AdVEGF-A occurs through cell proliferation (black arrowheads). Scale bar = 50 µ m. (B and G) Longitudinal contrast-enhanced ultrasound imaging of rabbit thighs shows that perfusion is increased up to 27-fold 6 days after AdVEGF-A gene transfer in the target muscle (inside brackets). (C and H) 3-dimensional (3D) reconstructions of the ultrasound data show the increase in blood flow in the whole vascular tree, including large vessels. (D and I) Transversal mid-thigh T₂*-weighted magnetic resonance imaging (MRI) using a superparamagnetic contrast agent (Resovist), which causes intensive signal loss in the AdVEGF-A transduced semimembranosus muscle (outlined with dashed lines) as the result of high contrast concentration, i.e., blood volume. (E and J) Blood volume MRI maps visualize the difference in blood volume between AdVEGF-A and AdLacZ-treated muscles. Muscle edema is obvious after AdVEGF-A gene transfer both in ultrasound and MRI. P = proximal end of the semimembranosus muscle; asterisks = free fluid in between muscles after AdVEGF-A gene transfer; white arrowheads = profound femoral artery; arrows = superficial femoral artery. The figure, excluding the insets, has been modified from Rissanen et al. (55) with the permission of Lippincott Williams & Wilkins.