Sympathetic Neurons Express and Secrete MMP-2 and MT1-MMP to Control Nerve Sprouting via Pro-NGF Conversion

Erol Saygili*, Patrick Schauerte, Maimouna Pekassa, Esra Saygili, Gediminas Rackauskas, Robert H. G. Schwinger, Joachim Weis, Christian Weber, Nikolaus Marx, Obaida R. Rana

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

Abstract

Recently, we have shown that high frequency electrical field stimulation (HFES) of sympathetic neurons (SN) induces nerve sprouting by up-regulation of nerve growth factor (NGF) which targets the tyrosine kinase A receptor (TrkA) in an autocrine/paracrine manner. There is increasing evidence that matrix metalloproteinase-2 (MMP-2) is not only involved in extracellular matrix (ECM) turnover but may also exert beneficial effects during neuronal growth. Therefore, this study aimed to investigate the regulation and function of MMP-2 and its major activator membrane type 1-matrix metalloproteinase (MT1-MMP) as well its inhibitor TIMP-1 in SN under conditions of HFES. Moreover, we analyzed molecular mechanisms of the beneficial effect of losartan, an angiotensin II type I receptor (AT-1)blocker on HFES-induced nerve sprouting. Cell cultures of SN from the superior cervical ganglia (SCG) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz. HFES increased MMP-2 and MT1-MMP mRNA and protein expression, whereas TIMP-1 expression remained unchanged. Under conditions of HFES, we observed a shift from pro- to active-MMP-2 indicating an increase in MMP-2 enzyme activity. Specific pharmacological MMP-2 inhibition contributed to an increase in pro-NGF amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth. Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced NGF, MMP-2, and MT1-MMP up-regulation. In summary, specific MMP-2 blockade prevents sympathetic nerve sprouting (SNS) by inhibition of pro-NGF conversion while losartan abolishes HFES-induced SNS by reducing total NGF, MMP-2 and MT1-MMP expression.
Original languageEnglish
Pages (from-to)17-25
JournalCellular and Molecular Neurobiology
Volume31
Issue number1
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Electrical stimulation
  • Sympathetic neurons
  • Nerve sprouting
  • MMP-2
  • NGF

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