Understanding the vascular physiology after exposure to ultrasound stimulated microbubble oscillations

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Provascular therapy, a promising approach to sensitize hypoxic tumor to radiotherapy, is hampered by the difficulty to target tumor vasculature using systemic approaches. Interestingly, it was recently shown that ultrasound stimulated microbubble (MB) oscillations can locally increase blood perfusion. Two new signaling pathways (nitric oxide and purinergic signaling) have been identified by the investigator (Dr Yu) and others to be implicated in this vasoactive response, but the conditions leading to their activation, the timecourse of the response and the cells implicated are largely unknown. Whereas the physical interactions between microbubbles and biological membranes have been studied before, the biological responses following MB interactions with cells, including the activation of vasoactive molecular signaling pathways, remain unexplored. In this research program, I (Dr Yu) will investigate nitric oxide and purinergic signaling, their time course, reservoir and interactions, at the cellular and vascular levels following exposure to microbubbles and ultrasound. More precisely, I will systematically study the effect of ultrasound stimulated MB oscillations on red blood cells and endothelial cells, the two cell types most likely to interact with MBs and that are known to participate in nitric oxide and purinergic regulation. The research program is composed of two objectives: in objective #1 we use basic in vitro cell culture for high throughput imaging experiments to investigate cellular pathway activation and their time course; in objective #2 we use ex vivo arterial vessel perfusion chambers experiments to assess the functional response in the presence of flow. The effect of ultrasound pulse length and pressure as well as microbubble concentration will be studied. Understanding the basic molecular mechanisms involved in microbubble mediated vasodilation, and their time course, will guide the development of targeted provascular radio-sensitization therapies against cancer and further our understanding of microbubble cell interactions from a biological and physiological perspective.