Susana F Rocha1, Maria Schiller2, Ding Jing2, Hang Li2, Stefan Butz2, Dietmar Vestweber2, Daniel Biljes2, Hannes C A Drexler2, Melina Nieminen-Kelhä2, Peter Vajkoczy2, Susanne Adams2, Rui Benedito2, Ralf H Adams2. 1. 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. 2. 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.).
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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.
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