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 beta2 integrin (CD18)-dependent mechanism.


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.


CONCLUSIONS
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.
Chappell
John C
JC
Department of Biomedical Engineering, University of Virginia, UVA Health System, Charlottesville, VA 22908, USA.
Song
Ji
J
Klibanov
Alexander L
AL
Price
Richard J
RJ
D000241:Adenosine; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001158:Arteries / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism*; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D002678:Chimera; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply; D006940:Hyperemia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D045423:Microbubbles; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D014465:Ultrasonics
D018821:CD18 Antigens; D000241:Adenosine