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Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells

  • Author(s): Yao, Jianhua S
  • Zhai, Wenwu
  • Fan, Yongfeng
  • Lawton, Michael T
  • Barbaro, Nicholas M
  • Young, William L
  • Yang, Guo-Yuan
  • et al.
Abstract

Interleukin- 6 ( IL- 6) may play multiple roles in angiogenesis and vascular remodeling. Our previous study showed that a promoter polymorphism ( 174G > C) in IL- 6 is associated with brain arteriovenous malformation hemorrhage; tissue expression is related to genotype. In this study, we investigated the effects of IL- 6 on human cerebral smooth muscle cells ( HCSMCs) and smooth muscle cells isolated from brain arteriovenous malformation surgical specimens ( AVM SMCs) and surgical controls ( control HCSMCs - from structurally normal temporal lobe taken during surgical treatment of epilepsy patients). We found that IL- 6 ( 1.16 +/- 0.27 versus 0.376 +/- 0.04 pg/ mL, n= 5, P < 0.05) and endogenous vascular endothelial growth factor ( VEGF) receptor II ( kinase domain- containing receptor ( KDR), 15 +/- 3 versus 1.5 +/- 3 pg/ mL, n= 5, P < 0 .05) were increased in brain AVM SMCs compared with control HCSMCs. Further research revealed that IL- 6 could stimulate SMC proliferation, VEGF release, and KDR activation in control HCSMCs. It could also stimulate KDR phosphorylation in control HCSMCs, further confirming a unique role of IL- 6 in the triggering of KDR. Interleukin- 6 could increase matrix metalloproteinase- 9 ( MMP- 9) secretion through activating KDR in control HCSMCs ( P < 0.05 versus control). Inhibiting IL- 6- induced KDR could reduce MMP- 9 activity at least 50% compared with the control group ( P < 0.05). Increased MMP- 9 activity was accompanied by increased control HCSMC proliferation, and blocking MMP- 9 activity significantly reduced IL- 6- induced control HCSMC proliferation ( P < 0.05). Collectively, our results show that IL- 6 could activate, amplify, and maintain the angiogenic cascade in HCSMCs. A novel role of IL- 6 during HCSMC proliferation is upregulating KDR expression and phosphorylation. The results may contribute to the angiogenic phenotype of human brain vascular diseases, such as brain AVM.

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