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The vasculature emerges as a potential therapeutic target in treating ADPKD liver cysts
September 24, 2009As part of an effort to develop effective medical therapies that block the progression of liver cyst growth in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), researchers at the University of Colorado Anschutz Medical Center have found that the liver cyst walls develop and maintain a vasculature as they grow out from the body of the liver and that factors released by epithelial cells that line the liver cyst wall lumen can drive the proliferation and development of vascular endothelial cells.
The findings, which appear in the October 2009 issue of Experimental Biology and Medicine, are the result of a multi-disciplinary team assembled by Dr. Brian Doctor. Dr. Nick Barry, a biophysicist, and Dr. Ryan McWilliams, a medical resident, employed complimentary imaging techniques to visualize and characterize the vasculature within native liver cyst walls of human ADPKD patients and pkd2(WS25/-) mice, an orthologous mouse model of ADPKD. Kelley Brodsky, a senior research associate, and Dr. Claudia Amura, a cell biologist, then used in vitro assays of endothelial cell proliferation and vascular development to demonstrate that human liver cyst fluids, which contain a variety of cytokines and growth factors secreted by the liver cyst lining epithelium, are capable of driving the angiogenic phenotype of endothelial cells. Further, inhibition of VEGF receptor signaling dramatically impeded this angiogenic phenotype.
Dr. Doctor noted that "by establishing the presence of the vasculature within the enlarging liver cyst walls and defining the putative signaling pathways that induce angiogenesis within them, this study opens up an exciting new direction in the quest to develop medical therapies that can block the often devastating growth of liver cysts in patients with ADPKD".
In summary, while there are differences in their vascular density and distribution, both human ADPKD and pkd2(WS25/-) mouse liver cyst walls develop vascular structures as they grow out from the liver. In vitro studies demonstrate that angiogenic factors secreted by the liver cyst wall epithelium, including VEGF-A and IL-8, can drive angiogenic development of human endothelial cells. This development is blocked by inhibition of VEGF receptor signaling. Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "The article by Brodsky and colleagues provides the important insight that the liver cyst walls maintain a vasculature as they grow out from the liver and that VEGF receptor signaling plays a key role in inducing angiogenesis. These multidisciplinary studies lay a framework for the development of new therapies aimed at preventing the growth of liver cysts in patients with ADPKD".
Society for Experimental Biology and Medicine
In summary, while there are differences in their vascular density and distribution, both human ADPKD and pkd2(WS25/-) mouse liver cyst walls develop vascular structures as they grow out from the liver. In vitro studies demonstrate that angiogenic factors secreted by the liver cyst wall epithelium, including VEGF-A and IL-8, can drive angiogenic development of human endothelial cells. This development is blocked by inhibition of VEGF receptor signaling. Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "The article by Brodsky and colleagues provides the important insight that the liver cyst walls maintain a vasculature as they grow out from the liver and that VEGF receptor signaling plays a key role in inducing angiogenesis. These multidisciplinary studies lay a framework for the development of new therapies aimed at preventing the growth of liver cysts in patients with ADPKD".
Society for Experimental Biology and Medicine
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