title: Mechanical stretch of sympathetic neurons induces VEGF expression via a NGF and CNTF signaling pathway.
abstract: Mechanical stretch has been shown to increase vascular endothelial growth factor (VEGF) expression in cultured myocytes. Sympathetic neurons (SN) also possess the ability to express and secrete VEGF, which is mediated by the NGF/TrkA signaling pathway. Recently, we demonstrated that SN respond to stretch with an upregulation of nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Whether stretch increases neuronal VEGF expression still remains to be clarified. Therefore, SN from the superior cervical ganglia of neonatal Sprangue Dawley rats were exposed to a gradual increase of stretch from 3% up to 13% within 3days (3%, 7% and 13%). Under these conditions, the expression and secretion of VEGF was analyzed. Mechanical stretch significantly increased VEGF mRNA and protein expression (mRNA: control=1 vs. stretch=3.1; n=3/protein: control=1 vs. stretch=2.7; n=3). ELISA experiments to asses VEGF content in the cell culture supernatant showed a time and dose dependency in VEGF increment due to stretch. NGF and CNTF neutralization decreased stretch-induced VEGF augmentation in a significant manner. This response was mediated in part by TrkA receptor activation. The stretch-induced VEGF upregulation was accompanied by an increase in HIF-1α expression. KDR levels remained unchanged under conditions of stretch, but showed a significant increase due to NGF neutralization. In summary, SN respond to stretch with an upregulation of VEGF, which is mediated by the NGF/CNTF and TrkA signaling pathway paralleled by HIF-1α expression. NGF signaling seems to play an important role in regulating neuronal KDR expression.
authors.affiliation: Department of Cardiology, University RWTH Aachen, Aachen, Germany. esaygili@ukaachen.de
authors.forename: Erol
authors.initials: E
authors.lastname: Saygili
authors.forename: Maimouna
authors.initials: M
authors.lastname: Pekassa
authors.forename: Esra
authors.initials: E
authors.lastname: Saygili
authors.forename: Gediminas
authors.initials: G
authors.lastname: Rackauskas
authors.forename: Dorothee
authors.initials: D
authors.lastname: Hommes
authors.forename: Fawad
authors.initials: F
authors.lastname: Noor-Ebad
authors.forename: Christopher
authors.initials: C
authors.lastname: Gemein
authors.forename: Matthias D H
authors.initials: MD
authors.lastname: Zink
authors.forename: Robert H G
authors.initials: RH
authors.lastname: Schwinger
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.forename: Patrick
authors.initials: P
authors.lastname: Schauerte
authors.forename: Obaida R
authors.initials: OR
authors.lastname: Rana
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D032383:Myocytes, Cardiac / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013564:Sympathetic Nervous System / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D020934:Ciliary Neurotrophic Factor; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D020932:Nerve Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2