title: Esm1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability.
abstract: BACKGROUND
  Endothelial cell-specific molecule 1 (Esm1) is a secreted protein thought to play a role in angiogenesis and inflammation. However, there is currently no direct in vivo evidence supporting a function of Esm1 in either of these processes.
  
  
  OBJECTIVE
  To determine the role of Esm1 in vivo and the underlying molecular mechanisms.
  
  
  RESULTS
  We generated and analyzed Esm1 knockout (Esm1(KO)) mice to study its role in angiogenesis and inflammation. Esm1 expression is induced by the vascular endothelial growth factor A (VEGF-A) in endothelial tip cells of the mouse retina. Esm1(KO) mice showed delayed vascular outgrowth and reduced filopodia extension, which are both VEGF-A-dependent processes. Impairment of Esm1 function led to a decrease in phosphorylated Erk1/2 (extracellular-signal regulated kinases 1/2) in sprouting vessels. We also found that Esm1(KO) mice displayed a 40% decrease in leukocyte transmigration. Moreover, VEGF-induced vascular permeability was decreased by 30% in Esm1(KO) mice and specifically on stimulation with VEGF-A165 but not VEGF-A121. Accordingly, cerebral edema attributable to ischemic stroke-induced vascular permeability was reduced by 50% in the absence of Esm1. Mechanistically, we show that Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A165 leading to increased bioavailability of VEGF-A165 and subsequently enhanced levels of VEGF-A signaling.
  
  
  CONCLUSIONS
  Esm1 is simultaneously a target and modulator of VEGF signaling in endothelial cells, playing a role in angiogenesis, inflammation, and vascular permeability, which might be of potential interest for therapeutic applications.
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.). sf.rocha@gmail.com.
authors: Susana F
authors: SF
authors: Rocha
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Maria
authors: M
authors: Schiller
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Ding
authors: D
authors: Jing
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Hang
authors: H
authors: Li
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Stefan
authors: S
authors: Butz
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Dietmar
authors: D
authors: Vestweber
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Daniel
authors: D
authors: Biljes
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Hannes C A
authors: HC
authors: Drexler
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Melina
authors: M
authors: Nieminen-Kelhä
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Peter
authors: P
authors: Vajkoczy
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Susanne
authors: S
authors: Adams
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Rui
authors: R
authors: Benedito
authors: From the Max Planck Institute for Molecular Biomedicine, Münster, Germany (S.F.R., M.S., D.J., H.L., S.B., D.V., D.B., H.C.A.D., S.A., R.B., R.H.A.); University of Münster, Münster, Germany (R.H.A.); Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.F.R., R.B.); and Neurochirurgische Klinik, Charite Universitätsmedizin, Berlin, Germany (M.N.-K., P.V.).
authors: Ralf H
authors: RH
authors: Adams
mesh_terms: D000818:Animals; D001682:Biological Availability; D002462:Cell Membrane / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology; D011509:Proteoglycans / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
chemical_list: D005353:Fibronectins; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C517044:endothelial cell-specific molecule-1, mouse
keywords: angiogenesis; capillary permeability; stroke; vascular endothelial growth factor A