Cellular and Molecular Neurobiology

, Volume 31, Issue 1, pp 17–25 | Cite as

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
Original Research


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.


Electrical stimulation Sympathetic neurons Nerve sprouting MMP-2 NGF 



Atrial fibrillation


Angiotensin receptor blocker


Angiotensin II type I receptor


Growth-associated protein-43


High frequency electrical field stimulation


Myocardial infarction


Matrix metalloproteinase-2


Membrane type 1-matrix metalloproteinase


Nerve growth factor


Renin–angiotensin system


Sudden cardiac death


Superior cervical ganglia


Sympathetic neurons


Sympathetic nerve sprouting


Tyrosin kinase A receptor


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Erol Saygili
    • 1
  • Patrick Schauerte
    • 1
  • Maimouna Pekassa
    • 1
  • Esra Saygili
    • 1
  • Gediminas Rackauskas
    • 1
  • Robert H. G. Schwinger
    • 2
  • Joachim Weis
    • 3
  • Christian Weber
    • 4
  • Nikolaus Marx
    • 1
  • Obaida R. Rana
    • 1
  1. 1.Department of Cardiology, Medical Clinic IRWTH Aachen UniversityAachenGermany
  2. 2.Medical Clinic IIKlinikum WeidenWeidenGermany
  3. 3.Institute for NeuropathologyRWTH Aachen UniversityAachenGermany
  4. 4.Institute for Molecular Cardiovascular ResearchRWTH Aachen UniversityAachenGermany

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