The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXCchemokine-induced angiogenic activity

We have previously shown that members of the ELR+ CXC chemokine family, inc luding IL-8; growth-related oncogenes alpha, beta, and gamma; granulocyte c hemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovasculariz ation mediated by these ELR+ CXC chemokines has not been determined. Becaus e all ELR+ CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypo thesized that CXCR2 is the putative receptor for ELR+ CXC chemokine-mediate d angiogenesis. To test this postulate, we first determined whether culture d human microvascular endothelial cells expressed CXCR2, CXCR2 was detected in human microvascular endothelial cells at the protein level by both West ern blot analysis and immunohistochemistry using polyclonal Abs specific fo r human CXCR2, To determine whether CXCR2 played a functional role in angio genesis, we determined whether this receptor was involved in endothelial ce ll chemotaxis, We found that microvascular endothelial cell chemotaxis in r esponse to ELR+ CXC chemokines was inhibited by anti-CXCR2 Abs. In addition , endothelial cell chemotaxis in response to ELR+ CXC chemokines was sensit ive to pertussis toxin, suggesting a role for G protein-linked receptor mec hanisms in this biological response. The importance of CXCR2 in mediating E LR+ CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR+ CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in t he corneas of CXCR2(-/-) mice.-We thus conclude that CXCR2 is the receptor responsible for ELR+ CXC chemokine-mediated angiogenesis.