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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2128.)
© 2005 American Heart Association, Inc.

Vascular Biology

Targeted Delivery of Bone Marrow Mononuclear Cells by Ultrasound Destruction of Microbubbles Induces Both Angiogenesis and Arteriogenesis Response

Takanobu Imada; Tetsuya Tatsumi; Yasukiyo Mori; Takashi Nishiue; Masayuki Yoshida; Hiroya Masaki; Mitsuhiko Okigaki; Hiroyuki Kojima; Yoshihisa Nozawa; Yasunobu Nishiwaki; Noriko Nitta; Toshiji Iwasaka; Hiroaki Matsubara

From the Department of Medicine II (T. Imada, Y.M., T.N., H. Masaki, T. Iwasaka) and Radiology (H.K.), Kansai Medical University, Osaka; the Department of Cardiovascular Medicine (T.T., M.O., H. Matsubara), Kyoto Prefectural University School of Medicine, Kyoto; the Department of Medical Biochemistry (M.Y., Y. Nishiwaki, N.N.), Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo; and the Pharmacobioregulation Research Laboratory (Y. Nozawa), Taiho Pharmaceutical Co Ltd, Saitama, Japan.

Correspondence to Hiroaki Matsubara MD, Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kamigyo-ku, Kyoto, 602-8566, Japan. E-mail matsubah{at}koto.kpu-m.ac.jp

Objective— Ultrasound (US)-mediated destruction of contrast microbubbles causes capillary rupturing that stimulates arteriogenesis, whereas intramuscular implantation (im) of bone marrow mononuclear cells (BM-MNCs) induces angiogenesis. We therefore studied whether US-targeted microbubble destruction combined with transplantation of BM-MNCs can enhance blood flow restoration by stimulating both angiogenesis and arteriogenesis.

Methods and Results— US-mediated destruction of phospholipid-coated microbubbles was applied onto ischemic hindlimb muscle and subsequently BM-MNCs were transfused. A significant enhancement in blood flow recovery after Bubble+US+BM-MNC infusion (34% increase, P<0.05) was observed compared with Bubble+US (25%). The ratio of capillary/muscle fiber increased by Bubble+US+BM-MNC-i.v (260%, P<0.01) than that in the Bubble+US group (172%), into which BM-MNCs were incorporated (angiogenesis). Smooth muscle -actin–positive arterioles were also increased, and angiography showed augmented collateral vessel formation (arteriogenesis). Platelet-derived proinflammatory factors activated by Bubble+US induces the expression of adhesion molecules (P-selectin and ICAM-1), leading to the attachment of transplanted BM-MNCs on the endothelium. Flow assay confirmed that the platelet-derived factors cause the adhesion of BM-MNCs onto endothelium under laminar flow.

Conclusions— This study demonstrates that the targeted delivery of BM-MNCs by US destruction of microbubbles enhances regional angiogenesis and arteriogenesis response, in which the release of platelet-derived proinflammatory factors activated by Bubble+US play a key role in the attachment of transplanted BM-MNCs onto the endothelial layer.

Ultrasound (US)-targeted microbubble destruction combined with transplantation of bone marrow mononuclear cells (BM-MNCs) enhances blood flow restoration by stimulating both angiogenesis and arteriogenesis. Release of proinflammatory factors from platelets activated by Bubble+US play a key role for adhesion of BM-MNCs on endothelium. This cell delivery system is efficient for therapeutic angiogenesis and arteriogenesis.

Key Words: angiogenesis • vasculogenesis • stem cell • endothelial progenitor cell • ultrasound

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