title: Fibrinogen-induced increased pial venular permeability in mice.
abstract: Elevated blood level of Fibrinogen (Fg) is commonly associated with vascular dysfunction. We tested the hypothesis that at pathologically high levels, Fg increases cerebrovascular permeability by activating matrix metalloproteinases (MMPs). Fibrinogen (4 mg/mL blood concentration) or equal volume of phosphate-buffered saline (PBS) was infused into male wild-type (WT; C57BL/6J) or MMP-9 gene knockout (MMP9-/-) mice. Pial venular leakage of fluorescein isothiocyanate-bovine serum albumin to Fg or PBS alone and to topically applied histamine (10(-5) mol/L) were assessed. Intravital fluorescence microscopy and image analysis were used to assess cerebrovascular protein leakage. Pial venular macromolecular leakage increased more after Fg infusion than after infusion of PBS in both (WT and MMP9-/-) mice but was more pronounced in WT compared with MMP9-/- mice. Expression of vascular endothelial cadherin (VE-cadherin) was less and plasmalemmal vesicle-associated protein-1 (PV-1) was greater in Fg-infused than in PBS-infused both mice groups. However, in MMP9-/- mice, VE-cadherin expression was greater and PV-1 expression was less than in WT mice. These data indicate that at higher levels, Fg compromises microvascular integrity through activation of MMP-9 and downregulation of VE-cadherin and upregulation of PV-1. Our results suggest that elevated blood level of Fg could have a significant role in cerebrovascular dysfunction and remodeling.
authors: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, Kentucky 40202, USA.
authors: Nino
authors: N
authors: Muradashvili
authors: Natia
authors: N
authors: Qipshidze
authors: Charu
authors: C
authors: Munjal
authors: Srikanth
authors: S
authors: Givvimani
authors: Richard L
authors: RL
authors: Benton
authors: Andrew M
authors: AM
authors: Roberts
authors: Suresh C
authors: SC
authors: Tyagi
authors: David
authors: D
authors: Lominadze
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015820:Cadherins / Q000096:biosynthesis; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis; D002550:Cerebral Veins / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000494:pharmacology* / Q000502:physiology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D007261:Infusions, Intra-Arterial; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D015854:Up-Regulation; D014699:Venules / Q000187:drug effects / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D002352:Carrier Proteins; D005340:Fibrinogen; D016650:Fluorescein-5-isothiocyanate; D020780:Matrix Metalloproteinase 9; D008565:Membrane Proteins; D012710:Serum Albumin, Bovine; D000099152:Cadherin 5; C486772:Plvap protein, mouse; C039217:fluorescein isothiocyanate bovine serum albumin; C501830:Mmp9 protein, mouse