Published Online
on December 16, 2002

A more recent version of this article appeared on January 28, 2003

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Submitted on August 15, 2002
Revised on September 27, 2002
Accepted on October 1, 2002

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

Howard Leong-Poi MD, Jonathan Christiansen MB ChB, Alexander L. Klibanov PhD, Sanjiv Kaul MD, and Jonathan R. Lindner MD^*

From the Cardiovascular Imaging Center, Cardiovascular Division, University of Virginia, Charlottesville.

^* To whom correspondence should be addressed. E-mail: jlindner{at}virginia.edu.

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 _v-integrins.

Methods and Results—Microbubbles targeted to _v-integrins were prepared by conjugating echistatin (MB_E) or monoclonal antibody against murine _v (MB) to their surface. Control microbubbles (MB_c) 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 (P<0.01) for MB_E (11±6 mm^-3) and MB (10±7 mm^-3) than that for MB_c (1±1 mm^-3). Retained MB_E and MB 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 _v-integrins. CEU demonstrated greater (P<0.01) acoustic intensity for MB_E (16.0±5.9 U) and MB (17.0±5.5 U) compared with MB_c (5.8±2.6 U). The signal from targeted microbubbles (MB_E and MB) correlated well (r=0.90) with the matrigel blood volume determined by CEU perfusion imaging.

Conclusions—CEU with microbubbles targeted for _v-integrins may provide a noninvasive method for assessing therapeutic angiogenesis.

Key words: angiogenesis • echocardiography • microcirculation

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