title: Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparanase.
abstract: BACKGROUND
  The vascular endothelial growth factor (VEGF) decoy receptor soluble VEGF-R1 (sVEGF-R1) is thought to protect the cells that produce it from adverse VEGF signaling. To accomplish this role, a mechanism for pericellular retention of sVEGF-R1 is required. Local retention may also prevent the accumulation of high circulating levels of sVEGF-R1 and resulting interference with homeostatic VEGF functions in remote organs.
  
  
  OBJECTIVE
  To reveal natural storage depots of sVEGF-R1 and determine mechanisms underlying its pericellular retention. To uncover natural mechanisms regulating its systemic release.
  
  
  RESULTS
  We show that both the canonical and human-specific isoforms of sVEGF-R1 are strongly bound to heparin. sVEGF-R1 produced by vascular smooth muscle cells is stored in the vessel wall and can be displaced from isolated mouse aorta by heparin. Another major reservoir of sVEGF-R1 is the placenta. Heparin increases the level of sVEGF-R1 released by cultured human placental villi, and pregnant women treated with low molecular weight heparin showed markedly elevated levels of sVEGF-R1 in the circulation. Heparanase is expressed in human placenta at the same locales as sVEGF-R1, and its transgenic overexpression in mice resulted in a marked increase in the levels of circulating sVEGF-R1. Conversely, heparanase inhibition, by either a neutralizing antibody or by inhibition of its maturation, reduced the amounts of sVEGF-R1 released from human placental villi, indicating a natural role of heparanase in sVEGF-R1 release.
  
  
  CONCLUSIONS
  Together, the findings uncover a new level of regulation governing sVEGF-R1 retention versus release and suggest that manipulations of the heparin/heparanase system could be harnessed for reducing unwarranted release of sVEGF-R1 in pathologies such as preeclampsia.
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Sela
authors.forename: Shira
authors.initials: S
authors.lastname: Natanson-Yaron
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Simcha
authors.initials: S
authors.lastname: Yagel
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010920:Placenta / Q000098:blood supply / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D005966:Glucuronidase; D006493:Heparin; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099175:Heparanase; C467484:VEGFA protein, human