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LAMMP Seminar Video
Combined Laser and Topical Rapamycin Treatment of Pathological Angiogenesis
Thuy L. Phung, MD, PhD

Vascular anomalies such as port wine stain (PWS) are congenital defects in blood vessel development and proliferation. Laser therapy is the mainstay of PWS treatment; however, most PWS are unresponsive to treatment or recur after laser therapy. The recurrence suggests regrowth of previously ablated blood vessels. This process is poorly understood, but likely involves angiogenesis under the regulation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF). The Akt/mTOR signaling pathway is the major pathway activated by VEGF that controls endothelial cell proliferation and survival. This pathway can be inhibited by the FDA-approved mTOR inhibitor rapamycin, which has anti-angiogenic properties that block VEGF production, endothelial cell proliferation and vascular permeability. We have shown in a hamster window chamber model that following laser irradiation of normal skin blood vessels, application of topical rapamycin suppressed the reformation and reperfusion of blood vessels previously disrupted by photothermolysis. Similarly, topical rapamycin blocked cell proliferation and revascularization in normal human skin after laser exposure. To demonstrate the effects of rapamycin in pathological vessels, we used a transgenic mouse model that recapitulates essential features of pathological angiogenesis through endothelial cell-specific hyperactivation of Akt. Using this animal model, we showed that the combined use of pulsed dye laser to induce blood vessel injury, and topical rapamycin to inhibit angiogenesis prevents the recurrence of abnormal blood vessels following laser treatment. The study provides strong preclinical evidence for the development of novel approaches involving anti-angiogenic agents in adjunct to laser therapy to improve therapeutic outcome in patients with PWS and possibly other types of vascular anomalies.

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