Noninvasive Assessment of Angiogenesis by Ultrasound and Microbubbles Targeted to α v -Integrins

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Abstract
Background— Noninvasive methods for characterizing neovessel formation during angiogenesis are currently lacking. We hypothesized that angiogenesis could be imaged with the use of contrast-enhanced ultrasound (CEU) with microbubbles targeted to αv-integrins. Methods and Results— Microbubbles targeted to αv-integrins were prepared by conjugating echistatin (MBE) or monoclonal antibody against murine αv (MBα) to their surface. Control microbubbles (MBc) were also prepared. The microvascular behavior of these microbubbles was assessed by intravital microscopy of the cremaster muscle in mice treated for 4 days with sustained-release FGF-2. Microvascular retention was much greater (PE (11±6 mm−3) and MBα (10±7 mm−3) than that for MBc (1±1 mm−3). Retained MBE and MBα attached directly to the microvascular endothelial surface. Microbubble retention in 4 control mice was minimal. Subcutaneous matrigel plugs enriched with FGF-2 were created in 12 mice and studied 10 days later. Neovessels within the matrigel stained positive for αv-integrins. CEU demonstrated greater (PE (16.0±5.9 U) and MBα (17.0±5.5 U) compared with MBc (5.8±2.6 U). The signal from targeted microbubbles (MBE and MBα) correlated well (r=0.90) with the matrigel blood volume determined by CEU perfusion imaging. Conclusions— CEU with microbubbles targeted for αv-integrins may provide a noninvasive method for assessing therapeutic angiogenesis.
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