Genomic regulation of angiogenesis in mouse lung.

摘要

A better understanding of the regulation of factors that promote and inhibit angiogenesis may ultimately enable improved therapeutic control of this important process. In this study we utilize a unique mouse model that allows study of the signalings of both processes in the lung within individual animals. The lung is unique in that angiogenesis takes place in an ischemic but hyperoxic environment and the new vasculature is from systemic (bronchial or intercostal), not the pulmonary vasculature. Such an anatomic separation allows the independent investigation of the mediators of ischemic tissues from the source of neovascularization. Obstruction of the left pulmonary artery following lateral thoracotomy 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. Pulmonary ischemia is essential since sham-operated thoracotomy does not result in lung angiogenesis. 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, quantitative real-time RT-PCR and enzyme-linked immunosorbent assay were used to compare the signals from these two lung regions in the first 14 days following ischemia. The findings reveal 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. Additionally, within the same animal model, the altered gene profiles of expression in the wounded thoracic wall overlying lung ischemia revealed the different signaling pattern from the neovascularization in normal wound healing. These observations suggest cross communication of the thoracic wall undergoing wound repair with the ischemic lung, providing important new information involved in promoting new blood vessel formation to the lung.