The role of CXCR2 in systemic neovascularization of the mouse lung

Abstract

We previously showed increased expression of the ELR+, CXC chemokines in the lung after left pulmonary artery obstruction. These chemokines have been shown in other systems to bind their G protein-coupled receptor, CXCR2, and promote systemic endothelial cell proliferation, migration, and capillary tube formation. In the present study, we blocked CXCR2 in vivo using a neutralizing antibody and also studied mice that were homozygous null for CXCR2. To estimate the extent of neovascularization in this model, we measured systemic blood flow to the left lung 14 days after left pulmonary artery ligation (LPAL). We found blood flow significantly reduced (67% decrease) with neutralizing antibody treatment compared with controls. However, blood flow was not altered in the CXCR2-deficient mice compared with wild-type controls after LPAL. To test for ligand availability, we measured macrophage inflammatory protein (MIP)-2 in lung homogenates after LPAL, because this is the predominant CXC chemokine previously shown to be increased after LPAL ( 22 ). MIP-2 protein was two- to fourfold higher in the left lung relative to the right lung in all treatment groups 4 h after LPAL and this increase did not differ among groups. We speculate that the CXCR2-deficient mice have compensatory mechanisms that mitigate their lack of gene expression and conclude that CXCR2 contributes to chemokine-induced systemic angiogenesis after pulmonary artery obstruction.