title: Endothelial surface layer degradation by chronic hyaluronidase infusion induces proteinuria in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Functional studies show that disruption of endothelial surface layer (ESL) is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model.
  
  
  METHODS
  Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 weeks received continuous active or heat-inactivated hyaluronidase (10 U/hr, i.v.) through an osmotic minipump during 4 weeks. Blood chemistry and anatomic changes in both macrovasculature and kidneys were examined.
  
  
  RESULTS
  Infusion with active hyaluronidase resulted in decreased ESL (0.32±0.22 mL) and plasma volume (1.03±0.18 mL) compared to inactivated hyaluronidase (0.52±0.29 mL and 1.28±0.08 mL, p<0.05 respectively).Active hyaluronidase increased proteinuria compared to inactive hyaluronidase (0.27±0.02 vs. 0.15±0.01 µg/µg protein/creatinin, p<0.05) without changes in glomerular morphology or development of tubulo-interstitial inflammation. Atherosclerotic lesions in the aortic branches showed increased matrix production (collagen, 32±5 vs. 18±3%; glycosaminoglycans, 11±5 vs. 0.1±0.01%, active vs. inactive hyaluronidase, p<0.05).
  
  
  CONCLUSIONS
  ESL degradation in apoE deficient mice contributes to reduced increased urinary protein excretion without significant changes in renal morphology. Second, the induction of compositional changes in atherogenic plaques by hyaluronidase point towards increased plaque vulnerability. These findings support further efforts to evaluate whether ESL restoration is a valuable target to prevent (micro) vascular disease progression.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Marijn C
authors.initials: MC
authors.lastname: Meuwese
authors.forename: Lysette N
authors.initials: LN
authors.lastname: Broekhuizen
authors.forename: Mayella
authors.initials: M
authors.lastname: Kuikhoven
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: Hans
authors.initials: H
authors.lastname: Vink
authors.forename: Bernard M
authors.initials: BM
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology*; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D011507:Proteinuria / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D006821:Hyaluronoglucosaminidase