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Identification of Genes Promoting Angiogenesis in Mouse Lung by Transcriptional Profiling

Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Department of Environmental Health Sciences, Bloomberg School of Public Health, and Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Address correspondence to: Elizabeth M. Wagner, Ph.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, Maryland 21224. E-mail: wagnerem{at}jhmi.edu

A better understanding of the regulation of factors that promote angiogenesis may ultimately enable improved therapeutic control of this important process. In our previous studies, obstruction of the left pulmonary artery in the mouse consistently induced the formation of a new vasculature, which developed from the visceral pleura and entered the upper left lung directly within 5–6 days after ligation. No new vessels developed to the lower left lung, despite the initial ischemic stimulus being identical to that in the upper lung. Using this unique model of angiogenesis, we have determined the temporal pattern of differential gene expression from two independent regions of the same lung: one where angiogenesis is induced, and the other where angiogenesis does not occur. Microarray analysis and quantitative real-time RT-PCR were used to compare the signals from these two lung regions in the first 3 d following ischemia. The findings reveal the important roles of ELR⁺ CXC chemokines as proangiogenic signals. Genes involved in tissue remodeling, inflammation, and injury were also upregulated in the proangiogenic upper lung. Results also confirm that lung ischemia, rather than hypoxia, is the essential trigger for angiogenesis. These altered profiles of expression in the early stage of lung ischemia show potential roles and interactions of the most important genes involved in promoting new blood vessel formation.

Abbreviations: a disintegrin and metalloproteinase, ADAM • expressed sequence tags, ESTs • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • hypoxia-inducible factor, HIF • interleukin, IL • keratinocyte-derived chemokines, KC • lipopolysaccharide-induced CXC chemokines, LIX • lower left lung, LLL • left pulmonary artery, LPA • macrophage receptor with collagenous structure, MARCO • macrophage inflammatory protein 2, MIP-2 • right lung, RL • upper left lung, ULL

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