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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1117.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Ultrasonic Microbubble Destruction Stimulates Therapeutic Arteriogenesis Via the CD18-Dependent Recruitment of Bone Marrow–Derived Cells

John C. Chappell; Ji Song; Alexander L. Klibanov; Richard J. Price

From the Department of Biomedical Engineering (J.C.C., J.S., R.J.P.) and the Cardiovascular Division (A.L.K.), University of Virginia, Charlottesville.

Correspondence to Richard J. Price, PhD, Associate Professor, Department of Biomedical Engineering, University of Virginia, Box 800759, UVA Health System, Charlottesville, VA 22908. E-mail rprice{at}virginia.edu

Objective— We have previously shown that, under certain conditions, ultrasonic microbubble destruction creates arteriogenesis and angiogenesis in skeletal muscle. Here, we tested whether this neovascularization response enhances hyperemia in a rat model of arterial insufficiency and is dependent on the recruitment of bone marrow–derived cells (BMDCs) to treated tissues via a β2 integrin (CD18)-dependent mechanism.

Methods and Results— Sprague-Dawley rats, C57BL/6 wild-type mice, and C57BL/6 chimeric mice engrafted with BMDCs from either GFP⁺ or CD18^–/– mice received bilateral femoral artery ligations. Microbubbles (MBs) were intravenously injected, and one gracilis muscle was exposed to pulsed 1 MHz ultrasound (US). Rat hindlimbs exhibited significant increases in adenosine-induced hyperemia and arteriogenesis compared to contralateral controls at 14 and 28 days posttreatment. US-MB–treated wild-type C57BL/6 mice exhibited significant arteriogenesis, angiogenesis, and CD11b⁺ monocyte recruitment; however, these responses were all completely blocked in CD18^–/– chimeric mice. The number of BMDCs increased in US-MB–treated muscles of GFP⁺ chimeric mice; however, GFP⁺ BMDCs did not incorporate into microvessels as vascular cells.

Conclusion— In skeletal muscle affected by arterial occlusion, arteriogenesis and hyperemia can be significantly enhanced by ultrasonic MB destruction. This response depends on the recruitment, but not vascular incorporation, of BMDCs via a CD18-dependent mechanism.

Ultrasonic microbubble destruction represents a potential tool in therapeutic strategies, particularly in the targeted stimulation of neovascularization. In the current study, we demonstrate the ability of ultrasound-microbubble interactions to enhance arteriogenesis and perfusion in ischemic tissues through recruitment of marrow-derived cells via CD18. These observations support the development of ultrasound microbubble–based therapies.

Key Words: ultrasonics • contrast media • arteriogenesis • microcirculation • marrow-derived cells

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