A CCR2/CCR5 Antagonist Attenuates an Increase in Angiotensin II-Induced CD11b⁺ Monocytes from Atherogenic ApoE^−/− Mice

Monocyte infiltration into the vessel wall, a process primarily mediated by the interaction between monocyte chemoattractant protein-1 (MCP-1) and its receptor, CCR2, is a key step in atherogenesis. Angiotensin II (Ang II) enhances this monocyte infiltration by increasing the endothelial binding integrin, CD11b. However, the modulation of the Ang II-induced CD11b expression in monocytes in not clear. The aim of this study was to determine if MCP-1/MCP-2 receptor (CCR2) interaction regulates monocyte CD11b expression after 7 days of Ang II infusion.

In ApoE^−/− mice continuous subcutaneous infusion of Ang II (0.75 mg/kg/day) for 7 days significantly increased CD11b expression in circulating monocytes as measured by flow cytometry. CD11b expression in ApoE^−/− was increased from 135 ± 9 to 176 ± 12 mean fluorescent intensity (MFI), control and Ang II-treated, respectively while in C57B/J wildtype mice CD11b increased from 128 ± 13 to 174 ± 8 MFI, control and Ang II-treated, respectively. Interestingly, co-infusion of either MCP-1 neutralizing antibody (25 μg/kg/day) or a CCR2 antagonist (500 μg/kg/day) with Ang II for 7 days effectively inhibited monocyte CD11b expression and this inhibition was accompanied by a down-regulated vascular infiltration of Mac-2 positive monocyte-derived macrophages.

Our data in the atherogenic ApoE^−/− mouse demonstrates that the Ang II induced increase in both monocytic CD11b integrin expression and monocyte vascular infiltration occurs early in atherogenesis. These Ang II-induced monocytic changes are in part regulated through the MCP-1/CCR2 interaction.