Publication Date:
2016-02-24
Description:
Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21 Ras , and increases Ras signaling. Heterozygous Nf1 ( Nf1 +/– ) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1 +/– mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1 +/– mice. MCP-1 induces a dose-responsive increase in Nf1 +/– macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1 +/– SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1 +/– neointima formation, we induced neointima formation by carotid artery ligation in Nf1 +/– and WT mice with genetic deletion of either MCP1 or CCR2 . Loss of MCP-1 or CCR2 expression effectively inhibited Nf1 +/– neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1 +/– neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1 +/– monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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