title: Mechanism of VEGF-induced uterine venous hyperpermeability.
abstract: BACKGROUND
  Transfer of molecular signals from veins to adjacent arteries is an established mechanism of vascular communication in the uterine circulation, which ultimately depends on venous permeability. This study tests the hypotheses that: (1) uterine veins are permeable to intravenous solutes, using a 3-kDa dextran tracer and (2) this permeability is enhanced in response to vascular endothelial growth factor (VEGF). Additionally, the involvement of nitric oxide (NO), calcium, and the phospholipase C-protein kinase C (PLC-PKC) cascade in VEGF-enhanced permeability were investigated, and the impact of pregnancy-induced uterine vascular remodeling on permeability was evaluated.
  
  
  METHODS
  Studies utilized fluorimetry to quantitate solute flux in isolated segments of rat uterine vein as a function of endothelial surface area and time under basal and VEGF-stimulated conditions. VEGF signaling was probed using NO synthase inhibition (L-NNA), calcium channel blockade (lanthanum chloride) and withdrawal (calcium-free solution), and inhibitors of the PLC-PKC cascade (U-73122 and chelerythrine chloride, respectively). Gestational effects were assessed using vessels from late pregnant (day 20) rats.
  
  
  RESULTS
  Basal flux (control) in nonpregnant animals was 26 +/- 2.5 molecules/microm2/min x 1,000 and was increased significantly by VEGF in a concentration-dependent manner (1 nM approximately 3.3-fold, 10 nM approximately 4.6-fold). Inhibition of PLC, PKC, and calcium signaling, but not NO, attenuated the response to VEGF. Gestation significantly increased flux (78 +/- 9.3 molecules/microm2/min x 1,000), and maintained responsiveness to VEGF.
  
  
  CONCLUSIONS
  These results demonstrate uterine venous permeability to intermediate-sized solutes through a VEGF-sensitive pathway involving calcium and PLC-PKC, but not NO, and further substantiate a role for veno-arterial communication in uterine blood flow regulation during pregnancy.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Vermont College of Medicine, Burlington, VT 05405, USA. gcelia@physiology.med.uvm.edu
authors.forename: Gerard
authors.initials: G
authors.lastname: Celia
authors.forename: George
authors.initials: G
authors.lastname: Osol
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D009569:Nitric Oxide / Q000502:physiology; D011247:Pregnancy; D011493:Protein Kinase C / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D014680:Veins / Q000378:metabolism
chemical_list: D004963:Estrenes; D011760:Pyrrolidinones; D042461:Vascular Endothelial Growth Factor A; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D009569:Nitric Oxide; D011493:Protein Kinase C; D002118:Calcium