Ultrasound Contrast Agents Affect the Angiogenic Response

Abstract

Objectives The interaction of ultrasound contrast agents (UCAs) and ultrasound (US) provides a way to spatially and temporally target tissues. Recently, UCAs have been used therapeutically to induce localized angiogenesis. Ultrasound contrast agents, however, have been documented to induce negative bioeffects. To further understand the balance of risks and benefits of UCAs and to examine the mechanism of US‐UCA–induced angiogenesis, this study explored the role of UCAs, in particular Definity (Lantheus Medical Imaging, Inc, North Billerica, MA), in producing an angiogenic response. Methods The gracilis muscles of Sprague Dawley rats were exposed to 1‐MHz US. The rats were euthanized the same day or allowed to recover for 3 or 6 days post exposure (DPE). Ultrasound peak rarefactional pressures (P r s) of 0.25, 0.83, 1.4, and 2.0 MPa were used while rats were infused with either saline or Definity. Assessments for angiogenesis included capillary density, inflammation, and vascular endothelial growth factor (VEGF), both acutely (0 DPE) and at 3 and 6 DPE. Results The results of this study suggest that the angiogenic response is dependent on infusion media, P r , and DPE. While capillary density did not reach significance, VEGF expression was significant for infusion media, P r , and DPE with inflammation co‐occurrence ( P < .05). Conclusions These results suggest that the angiogenic response is elicited by a mechanical effect of US‐UCA stimulation of VEGF that is potentially optimized when collapse occurs.