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. 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 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.