title: Temporal regulation of venous extracellular matrix components during arteriovenous fistula maturation.
abstract: OBJECTIVE
  The venous limb of arteriovenous fistulae (AVF) adapts to the arterial environment by dilation and wall thickening; however, the temporal regulation of the expression of extracellular matrix (ECM) components in the venous limb of the maturing AVF has not been well characterized. We used a murine model of AVF maturation that recapitulates human AVF maturation to determine the temporal pattern of expression of these ECM components.
  
  
  METHODS
  Aortocaval fistulae were created in C57BL/6J mice and the venous limb was analyzed on postoperative days 1, 3, 7, 21, and 42. A gene microarray analysis was performed on day 7; results were confirmed by qPCR, histology, and immunohistochemistry. Proteases, protease inhibitors, collagens, glycoproteins, and other non-collagenous proteins were characterized.
  
  
  RESULTS
  The maturing AVF has increased expression of many ECM components, including increased collagen and elastin. Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP1) showed increased mRNA and protein expression during the first 7 days of maturation. Increased collagen and elastin expression was also significant at day 7. Expression of structural proteins was increased later during AVF maturation. Osteopontin (OPN) expression was increased at day 1 and sustained during AVF maturation.
  
  
  CONCLUSIONS
  During AVF maturation, there is significantly increased expression of ECM components, each of which shows distinct temporal patterns during AVF maturation. Increased expression of regulatory proteins such as MMP and TIMP precedes increased expression of structural proteins such as collagen and elastin, potentially mediating a controlled pattern of ECM degradation and vessel remodeling without structural failure.
authors.affiliation: 2 Department of Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut - USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hall
authors.forename: Kota
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Protack
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuneki
authors.forename: Go
authors.initials: G
authors.lastname: Kuwahara
authors.forename: Roland
authors.initials: R
authors.lastname: Assi
authors.forename: Kirstyn E
authors.initials: KE
authors.lastname: Brownson
authors.forename: Hualong
authors.initials: H
authors.lastname: Bai
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
authors.forename: Alan
authors.initials: A
authors.lastname: Dardik
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000379:methods*; D005109:Extracellular Matrix / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D014680:Veins / Q000378:metabolism / Q000601:surgery*