Targeted delivery of bone marrow mononuclear cells by ultrasound destruction of microbubbles induces both angiogenesis and arteriogenesis response.
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.


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 alpha-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.
Imada
Takanobu
T
Department of Medicine II, Kansai Medical University, Osaka, Japan.
Tatsumi
Tetsuya
T
Mori
Yasukiyo
Y
Nishiue
Takashi
T
Yoshida
Masayuki
M
Masaki
Hiroya
H
Okigaki
Mitsuhiko
M
Kojima
Hiroyuki
H
Nozawa
Yoshihisa
Y
Nishiwaki
Yasunobu
Y
Nitta
Noriko
N
Iwasaka
Toshiji
T
Matsubara
Hiroaki
H
D000792:Angiography; D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000000981:diagnostic imaging; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000379:methods*; D002196:Capillaries / Q000166:cytology / Q000000981:diagnostic imaging; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D019070:Cell Lineage; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000648:ultrastructure; D005263:Femoral Artery / Q000166:cytology / Q000000981:diagnostic imaging; D005269:Femur / Q000098:blood supply / Q000166:cytology; D007511:Ischemia / Q000000981:diagnostic imaging / Q000628:therapy*; D045423:Microbubbles; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D012039:Regional Blood Flow / Q000502:physiology; D018084:Ultrasonography, Interventional / Q000379:methods*
D015815:Cell Adhesion Molecules