The role of CXCR2 in systemic neovascularization of the mouse lung.
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, CXCR(2), and promote systemic endothelial cell proliferation, migration, and capillary tube formation. In the present study, we blocked CXCR(2) in vivo using a neutralizing antibody and also studied mice that were homozygous null for CXCR(2). 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 CXCR(2)-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 CXCR(2)-deficient mice have compensatory mechanisms that mitigate their lack of gene expression and conclude that CXCR(2) contributes to chemokine-induced systemic angiogenesis after pulmonary artery obstruction.
Sánchez
Jesús
J
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Moldobaeva
Aigul
A
McClintock
Jessica
J
Jenkins
John
J
Wagner
Elizabeth
E
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D008026:Ligation; D008168:Lung / Q000098:blood supply* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology*; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B