Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice
Jason C. Kovacic, … , Cynthia St. Hilaire, Manfred Boehm
Jason C. Kovacic, … , Cynthia St. Hilaire, Manfred Boehm
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):303-314. https://doi.org/10.1172/JCI40364.
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Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

Abstract

Inflammation is a key component of arterial injury, with VSMC proliferation and neointimal formation serving as the final outcomes of this process. However, the acute events transpiring immediately after arterial injury that establish the blueprint for this inflammatory program are largely unknown. We therefore studied these events in mice and found that immediately following arterial injury, medial VSMCs upregulated Rantes in an acute manner dependent on Stat3 and NF-κB (p65 subunit). This led to early T cell and macrophage recruitment, processes also under the regulation of the cyclin-dependent kinase inhibitor p21Cip1. Unique to VSMCs, Rantes production was initiated by Tnf-α, but not by Il-6/gp130. This Rantes production was dependent on the binding of a p65/Stat3 complex to NF-κB–binding sites within the Rantes promoter, with shRNA knockdown of either Stat3 or p65 markedly attenuating Rantes production. In vivo, acute NF-κB and Stat3 activation in medial VSMCs was identified, with acute Rantes production after injury substantially reduced in Tnfa–/– mice compared with controls. Finally, we generated mice with SMC-specific conditional Stat3 deficiency and confirmed the Stat3 dependence of acute Rantes production by VSMCs. Together, these observations unify inflammatory events after vascular injury, demonstrating that VSMCs orchestrate the arterial inflammatory response program via acute Rantes production and subsequent inflammatory cell recruitment.

Authors

Jason C. Kovacic, Rohit Gupta, Angela C. Lee, Mingchao Ma, Fang Fang, Claire N. Tolbert, Avram D. Walts, Leilani E. Beltran, Hong San, Guibin Chen, Cynthia St. Hilaire, Manfred Boehm

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Figure 3

Local vascular Rantes production regulates early CD3+ T cell and CD115+ macrophage infiltration and late neointimal formation following arterial injury.

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Local vascular Rantes production regulates early CD3+ T cell and CD115+ ...
(A) WT to WT and WT to Rantes–/– mice underwent arterial injury, and cell infiltration was assessed at 1 day. Relative CD3+ T cell infiltration was reduced in WT to Rantes–/– mice compared with WT to WT mice (n = 6 for WT to WT, n = 9 for WT to Rantes–/–; ****P < 0.0005). (B) Relative CD115+ macrophage infiltration was reduced 1 day after arterial injury in WT to Rantes–/– mice compared with WT to WT mice (n = 7 for WT to WT, n = 9 for WT to Rantes–/–; ****P < 0.0005). (C) Neointimal formation at 3 weeks after arterial injury, as assessed by intima/media ratio, was decreased in femoral vessels from WT to Rantes–/– as compared with WT to WT mice (n = 9 for WT to WT, n = 8 for WT to Rantes–/–; **P < 0.001). Data are shown as mean + SEM. (D) Representative cross sections of femoral arteries from WT to WT and WT to Rantes mice at 3 weeks after arterial wire injury (stained with H&E). Arrows indicate the internal elastic lamina. Scale bars: 100 μm.