This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/10/2128    most recent 01.ATV.0000179768.06206.cbv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Imada, T. Articles by Matsubara, H. Search for Related Content PubMed PubMed Citation Articles by Imada, T. Articles by Matsubara, H. Related Collections Angiogenesis

(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

This article has been cited by other articles:

				J. C. Chappell, J. Song, A. L. Klibanov, and R. J. Price Ultrasonic Microbubble Destruction Stimulates Therapeutic Arteriogenesis Via the CD18-Dependent Recruitment of Bone Marrow-Derived Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1117 - 1122. [Abstract] [Full Text] [PDF]

				T. Takahashi and H. Matsubara New Targeted Angiogenic Strategy: Bursting Bubbles Circ. Res., August 3, 2007; 101(3): 232 - 233. [Full Text] [PDF]

				H. Leong-Poi, M. A. Kuliszewski, M. Lekas, M. Sibbald, K. Teichert-Kuliszewska, A. L. Klibanov, D. J. Stewart, and J. R. Lindner Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF165 Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle Circ. Res., August 3, 2007; 101(3): 295 - 303. [Abstract] [Full Text] [PDF]