New targeted angiogenic strategy: bursting bubbles.

Although recent procedural advances in revascularization such as percutaneous coronary intervention and coronary artery bypass grafting improve quality of life and prognosis of the patients with ischemic diseases, these is still a subset of patients who are refractory to these conventional therapies and have poor prognosis. Therapeutic angiogenesis might offer a novel approach to these patients. Therapeutic angiogenesis involves an intervention to induce the formation of new blood vessels to restore the arterial blood and oxygen supply to ischemic tissues.1 Here, the term “angiogenesis” represents the process of new blood vessel formation in general (although the same term is also used to describe a more specific biological process in which the new capillaries sprout from preexisting vessels). Evolving knowledge of mechanisms of new blood vessel formation has raised the expectations for therapeutic angiogenesis as a treatment option. Recent studies have identified many angiogenic growth factors, vascular transcription factors, and the cells involved in neovascularization.1,2 Current potential strategies for therapeutic angiogenesis include delivering an angiogenic factor as a protein or a gene, and supplying cells which themselves are vascular progenitors or are releasing angiogenic factors. These strategies have worked in animal studies and in initial small scale openlabeled clinical trials. However, in larger, double-blinded controlled trials, therapeutic angiogenesis approaches have failed to show clinical benefits.1,2 Why? Perhaps there are subtle differences in angiogenesis between animals and humans, or the ischemic pathophysiology of animal models and human diseases are dissimilar. Another possibility is technical difficulties in translating the biology into the practice. In this issue of Circulation Research, Leon-Poi and colleagues report that targeted delivery of vascular endothelial growth factor (VEGF) gene using ultrasound-mediated destruction of cationic lipid microbubbles restores microvascular blood flow in a rat model of chronic hindlimb ischemia.3 Ultrasound-targeted microbubble destruction uses ultrasound contrast agents, mostly perfluorocarbon bubbles stabilized with albumin or a lipid shell. When insonified at high acoustic power, these agents oscillate, resulting in microbubble disintegration.4,5 This microbubble destruction has been shown to induce biophysical effects in the vicinity of contrast agents, and the therapeutic use of this phenomenon has been proposed for delivery of genes or drugs, and direct mechanical effects. One of the advantages of this method is that these bubbles cross the pulmonary circulation, so that the agents can be administrated intravenously, and reach any part of the body with arterial blood supply. And, at the desired sites, the agents can be activated or delivered by ultrasound. Leon-Poi et al coated the microbubbles with VEGFexpressing plasmid, intravenously administrated these bubbles, and then transferred the gene at the site of ischemia with ultrasound in hindlimb ischemia model.3 This model of ischemia is chronic, because the gene was transferred 14 days after common iliac artery ligation. Leon-Poi et al observed a significant increase in tissue perfusion mainly through the process of arteriogenesis, rather than angiogenesis in a narrow sense.3 Arteriogenesis refers to the maturation or de novo synthesis of collateral vessels. The effect of VEGF gene transfer with this method on arteriogenesis rather than angiogenesis is intriguing, as remodeling or development of collaterals could be much more effective than an increase in capillary bed to restore the blood flow in the setting of flowlimiting proximal conduit artery lesions. It will be an important issue to determine whether the preferential effect on arteriogenesis is associated with the method of gene delivery, ultrasonic destruction of microbubble destruction (Figure). Although the gene delivery is an important application of ultrasound-mediated microbubble destruction,4–6 use of this method is not limited to gene therapy. Acoustic cavitation leads to microbubble oscillation and collapse. Electron microscopic analysis showed transient pore formation on cell membrane immediately after microbubble destruction, called sonoporation.4,5 These mechanical effects facilitate entry of gene into the cells. At the same time, these mechanical forces affect nearby cells and tissues in vicinity of microbubble destruction. For example, microbubble destruction can facilitate thrombolysis in combination with thrombolytic agents such as urokinase and tissue plasminogen activator.7,8 Furthermore, ultrasoundmediated microbubble destruction itself can be angiogenic, as ultrasound-mediated microbubble destruction has been shown to be able to induce capillary rupture and increase the density of arterioles in ischemic muscle with local recruitment of VEGF producing inflammatory cells.9,10 Although capillary rupture with higher energies of ultrasound is just a step from adverse tissue damage, even with ultrasound without capillary rupture, ultrasound-mediated microbubble destruction has direct effects on vasculature and surrounding tissues. These effects can be The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Cardiovascular Medicine (T.T., H.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Experimental Therapeutics (T.T., H.M.), Translational Research Center, Kyoto University Hospital, Kyoto, Japan. Correspondence to Tomosaburo Takahashi, Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail [email protected] (Circ Res. 2007;101:232-233.) © 2007 American Heart Association, Inc.