title: A critical role for proinflammatory behavior of smooth muscle cells in hemodynamic initiation of intracranial aneurysm.
abstract: BACKGROUND
  Intracranial aneurysm initiation is poorly understood, although hemodynamic insult is believed to play an important role in triggering the pathology. It has recently been found in a rabbit model that while macrophages are absent during hemodynamic aneurysm initiation, matrix metalloproteinases (MMPs) are elevated and co-localize with smooth muscle cells (SMCs). This study investigates whether SMCs play a mechanistic role in aneurysm initiation triggered by hemodynamics.
  
  
  METHODS
  Aneurysmal damage was induced at the basilar terminus via bilateral common carotid artery ligation in rabbits (n = 45, plus 7 sham controls). 16 ligated rabbits were treated with doxycycline to inhibit MMPs, 7 received clodronate liposomes to deplete circulating monocytes, and the rest received no drug. Effects of the treatments on aneurysm development were assessed histologically 5 days and 6 months after ligation. MMP production and expression of inflammatory markers by SMCs was monitored by immunohistochemistry and in situ hybridization.
  
  
  RESULTS
  Treatment with doxycycline attenuated aneurysmal development examined at 5 days and 6 months, suggesting that MMPs contribute to aneurysm initiation. However, systemic depletion of macrophages did not decrease MMPs or suppress aneurysmal development. Immunofluorescence showed that during aneurysm initiation MMP-2 and MMP-9 were distributed in SMCs, and in situ hybridization indicated that they were transcribed by SMCs. In regions of early aneurysmal lesion, SMCs exhibited decreased expression of smooth muscle actin and increased NF-κB and MCP-1 expressions.
  
  
  CONCLUSIONS
  During aneurysm initiation triggered by hemodynamics, SMCs rather than macrophages are responsible for MMP production that is critical for aneurysmal lesion development. These SMCs exhibit proinflammatory behavior.
authors.affiliation: Department of Mechanical and Aerospace Engineering, State University of New York, Buffalo, New York, United States of America ; Toshiba Stroke and Vascular Research Center, State University of New York, Buffalo, New York, United States of America.
authors.forename: Max
authors.initials: M
authors.lastname: Mandelbaum
authors.forename: John
authors.initials: J
authors.lastname: Kolega
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dolan
authors.forename: Adnan H
authors.initials: AH
authors.lastname: Siddiqui
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002532:Intracranial Aneurysm / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline
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