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1 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: wagnerem{at}jhmi.edu.
The systemic vasculature in and surrounding the lung is proangiogenic while the pulmonary vasculature rarely participates in neovascularization. We studied the effects of the proangiogenic, ELR+, CXC chemokine MIP-2 (macrophage inflammatory protein-2) on endothelial cell proliferation and chemotaxis. Mouse aortic, pulmonary arterial, and lung microvascular endothelial cells were isolated and subcultured. Proliferation (3H-thymidine uptake) and migration (transwell chemotaxis) were evaluated in each cell type at baseline, upon exposure to MIP-2 (1-100 ng/ml) without and with exposure to hypoxia (24 hrs)-reoxygenation. Baseline proliferation did not vary among cell types and all cells showed increased proliferation after MIP-2. Aortic cell chemotaxis increased markedly upon exposure to MIP-2, however neither pulmonary artery nor lung microvascular endothelial cells responded to this chemokine. Assessment of CXCR2, the G-protein-coupled receptor through which MIP-2 signals, displayed no baseline difference in mRNA, protein, or cell surface expression among cell types. Exposure to hypoxia increased expression of CXCR2 of aortic endothelial cells only. Additionally, aortic cells compared to pulmonary cells, showed significantly greater protein and activity of cathepsin S, a proteolytic enzyme important for cell motility. Thus, the combined effects of increased cathepsin S activity providing increased motility, and enhanced CXCR2 expression after hypoxia, both contribute to the proangiogenic phenotype of systemic arterial endothelial cells.
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