Angiogenesis

The mechanical effects of focused ultrasound can interact with endothelial cells in a manner that induces angiogenesis – the process through which new blood vessels form from pre-existing vessels.1,2

This interaction causes the release of various angiogenic factors such as IL-8, bFGF, eNOS, and in particular VEGF.3,4 Microbubbles can be used to enhance this effect, and VEGF expression has been found to be positively correlated with the concentration of microbubbles administered.5,6 Possible mechanisms for this effect include intercellular communications with the endothelium and nearby cells4 and the activation and infiltration of immune cells that are capable of inducing neovascularization.7,8

Angiogenesis therapies have commonly been used in the treatment of chronic wounds, peripheral arterial disease, and ischemic heart disease.4,5 The drawbacks of current angiogenesis treatments for these disorders include invasiveness and non-specificity.5 Focused ultrasound may be able to overcome these obstacles by providing a non-invasive and targeted means of inducing angiogenesis.

Sources:

[1] Mizrahi, N., Seliktar, D. & Kimmel, E. Ultrasound-Induced Angiogenic Response in Endothelial Cells. Ultrasound Med. Biol. 33, 1818–1829 (2007). 

[2] Barzelai, S. et al. Low-intensity ultrasound induces angiogenesis in rat hind-limb ischemia. Ultrasound Med. Biol. 32, 139–145 (2006).. 

[3] Reher, P., Doan, N., Bradnock, B., Meghji, S. & Harris, M. EFFECT OF ULTRASOUND ON THE PRODUCTION OF IL-8, BASIC FGF AND VEGF. Cytokine 11, 416–423 (1999).

[4] Hanawa, K. et al. Low-Intensity Pulsed Ultrasound Induces Angiogenesis and Ameliorates Left Ventricular Dysfunction in a Porcine Model of Chronic Myocardial Ischemia. PLoS ONE 9, e104863 (2014).

[5] Johnson, C. A. & O’Brien, W. D. The angiogenic response is dependent on ultrasound contrast agent concentration. Vasc. Cell 4, 10 (2012). 

[6] Chappell, J. C., Klibanov, A. L. & Price, R. J. Ultrasound-microbubble-induced neovascularization in mouse skeletal muscle. Ultrasound Med. Biol. 31, 1411–1422 (2005).

[7] Miyake, Y. et al. Granulocyte colony-stimulating factor facilitates the angiogenesis induced by ultrasonic microbubble destruction. Ultrasound Med. Biol. 33, 1796–1804 (2007).

[8] Toyama, Y. et al. Ultrasound stimulation restores impaired neovascularization-related capacities of human circulating angiogenic cells. Cardiovasc. Res. 95, 448–459 (2012).