title: Vitronectin increases vascular permeability by promoting VE-cadherin internalization at cell junctions.
abstract: BACKGROUND
  Cross-talk between integrins and cadherins regulates cell function. We tested the hypothesis that vitronectin (VN), a multi-functional adhesion molecule present in the extracellular matrix and plasma, regulates vascular permeability via effects on VE-cadherin, a critical regulator of endothelial cell (EC) adhesion.
  
  
  RESULTS
  Addition of multimeric VN (mult VN) significantly increased VE-cadherin internalization in human umbilical vein EC (HUVEC) monolayers. This effect was blocked by the anti-α(V)β(3) antibody, pharmacological inhibition and knockdown of Src kinase. In contrast to mult VN, monomeric VN did not trigger VE-cadherin internalization. In a modified Miles assay, VN deficiency impaired vascular endothelial growth factor-induced permeability. Furthermore, ischemia-induced enhancement of vascular permeability, expressed as the ratio of FITC-dextran leakage from the circulation into the ischemic and non-ischemic hindlimb muscle, was significantly greater in the WT mice than in the Vn(-/-) mice. Similarly, ischemia-mediated macrophage infiltration was significantly reduced in the Vn(-/-) mice vs. the WT controls. We evaluated changes in the multimerization of VN in ischemic tissue in a mouse hindlimb ischemia model. VN plays a previously unrecognized role in regulating endothelial permeability via conformational- and integrin-dependent effects on VE-cadherin trafficking.
  
  
  CONCLUSIONS
  These results have important implications for the regulation of endothelial function and angiogenesis by VN under normal and pathological conditions.
authors.affiliation: Drug Discovery Research Center of Luzhou Medical College, Luzhou Medical College, Luzhou, Sichuan, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Meiping
authors.initials: M
authors.lastname: Ren
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.forename: Mao
authors.initials: M
authors.lastname: Luo
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D019096:Vitronectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D019096:Vitronectin; D019061:src-Family Kinases; D000099152:Cadherin 5; C467484:VEGFA protein, human