Ultrasonic microbubble destruction stimulates therapeutic arteriogenesis via the CD18-dependent recruitment of bone marrow-derived cells

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 beta 2 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.