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

Jianhua S. Yao, Wenwu Zhai, Yongfeng Fan, Michael T. Lawton, Nicholas M. Barbaro, William L. Young, Guo Yuan Yang

Research output: Contribution to journalArticle

38 Scopus citations

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 (1.1±0.27 versus 0.37±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.

Original languageEnglish (US)
Pages (from-to)510-520
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number3
DOIs
StatePublished - Mar 14 2007

Keywords

  • Angiogenesis
  • Human cerebral smooth muscle cell
  • Interleukin-6
  • Matrix metalloproteinase
  • Proliferation
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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