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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Research Article

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 2

Rantes production is acutely upregulated following arterial injury and produced locally by medial VSMCs.

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Rantes production is acutely upregulated following arterial injury and p...
(A) Local Rantes (left panel), p21Cip1 (middle panel), and Stat3 (right panel) mRNA expression after arterial injury by qRT-PCR. Comparisons shown are WT versus p21–/– at each respective time point for Rantes and Stat3, with p21Cip1 expression assessed in WT mice only. *P < 0.05; **P < 0.01; ***P < 0.0001. Also, in WT mice from baseline (uninjured) to 6 hours after injury, local vascular Rantes mRNA expression increased 21-fold (n = 5 both groups; P < 0.05); p21Cip1 mRNA expression increased 58-fold (n = 10 at baseline, n = 7 at 6 hours; P < 0.005); and Stat3 mRNA expression increased 3.5-fold (n = 7 at baseline, n = 12 at 6 hours; P < 0.001). (B) Representative confocal microscopic images of Rantes immunofluorescence staining of femoral artery sections from WT mice at baseline (uninjured) and 6 hours after injury. Rantes is shown in red, nuclei in blue (DAPI). Arterial elastic laminae are visible in green due to autofluorescence. Scale bars: 100 μm. (C) BM-transplanted mice were used to localize Rantes production 6 hours after arterial injury. By ANOVA (overall P = 0.0045), Rantes–/– mice reconstituted with WT BM (WT to Rantes–/–; n = 4) had decreased femoral artery Rantes mRNA expression in comparison with WT mice reconstituted with either WT (WT to WT, n = 6; *P < 0.05 versus WT to Rantes–/–) or Rantes–/– BM (Rantes–/– to WT, n = 5; *P < 0.05 versus WT to Rantes–/–). Data are shown as mean + SEM.