Ten-fold augmentation of endothelial uptake of vascular endothelial growth factor with ultrasound after systemic administration
Debabrata Mukherjee, MD*,
James Wong, MD, PhD*,
Brian Griffin, MD*,
Stephen G. Ellis, MD*,
Thomas Porter, MD ,
Subha Sen, PhD* and
James D. Thomas, MD, FACC*
* Cardiovascular Imaging Center, Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
Department of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Figure 1 Fluorescent microscopy (100x) revealed marked enhancement of VEGF uptake with US and PESDA. A) reveals minimal endothelial uptake of VEGF after intravenous injection of VEGF without ultrasound. B) reveals minimal fluorescence in the endothelium after injection of buffer solution without VEGF. C) reveals significant deposition of VEGF in the endothelial cells with PESDA and US, using a Langendorff preparation. D) reveals significant deposition of VEGF in the endothelial cells with PESDA and US, after intravenous injection in short-term in vivo experiments. E) reveals significant deposition of VEGF in the endothelial cells with US alone, using a Langendorff preparation. F) reveals significant deposition of VEGF in the endothelial cells with US alone, after intravenous injection in short-term in vivo experiments.
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Figure 2 Hematoxylin-eosin staining of an adjacent section revealed that the fluorescein-labeled VEGF is predominantly deposited in the endothelium of intramyocardial arterioles (100x).
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Figure 3 A) shows extensive coagulative necrosis and endothelial disruption with US power of 1.0 W/cm2 without PESDA (4,800x). B) shows endothelial pore formation with US power of 0.8 W/cm2 without PESDA (5,400x). C) (8,000x) shows no significant endothelial changes with US power of 0.6 W/cm2 as compared with control rat heart sections. D) shows a control rat heart section (4,800x).
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Figure 4 Immunohistochemistry showed marked increase in endothelial cell and smooth muscle cell count (not associated with a vascular lumen) in groups treated with US during administration of VEGF compared with groups treated with VEGF alone. A) shows endothelial cells as shown by vWF staining in a rat heart from an animal treated with VEGF alone and B) shows endothelial cells in a rat heart treated with VEGF + US. C) shows smooth muscle cells in a rat heart from an animal treated with VEGF alone and D) shows a rat heart from an animal treated with VEGF + US. Positively stained cells were counted at 200x.
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