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γ-secretase inhibitor up-regulates vascular endothelial growth factor receptor-2 and endothelial nitric oxide

Yu-Hui Zou1, Yi-Qun Cao, Lai-Xing Wang

  • 1Department of Neurosurgery, Changhai Hospital, Shanghai 200433, P.R. China.

Experimental and Therapeutic Medicine
|September 15, 2012
PubMed

Insights

γ-secretase inhibitors like DAPT enhance vascular endothelial growth factor receptor-2 (VEGFR-2) and endothelial nitric oxide synthase (eNOS) expression. This suggests combining inhibitors with eNOS or VEGF pathway disruption may improve anti-angiogenic tumor treatments.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • γ-secretase inhibitors suppress tumor growth via anti-angiogenesis.
  • The precise mechanisms regulating tumor angiogenesis by these inhibitors remain unclear.
  • Understanding these pathways is crucial for improving cancer therapies.

Purpose of the Study:

  • To investigate how γ-secretase inhibitors regulate vascular endothelial growth factor receptor (VEGFR) and endothelial nitric oxide synthase (eNOS).
  • To elucidate the role of VEGFR-2 in the regulation of eNOS by γ-secretase inhibitors.
  • To explore potential combination therapies for enhanced anti-angiogenic efficacy.

Main Methods:

  • Utilized H5V mouse microvascular endothelial cells treated with the γ-secretase inhibitor DAPT.
  • Measured protein and mRNA expression of VEGFRs (1, 2, 3) and eNOS using Western blotting and real-time PCR.
  • Employed a VEGFR-2 kinase inhibitor to assess the role of VEGFR-2 in eNOS regulation.

Main Results:

  • DAPT increased protein and mRNA expression of VEGFR-2 and eNOS.
  • DAPT decreased VEGFR-1 expression; VEGFR-3 was unaffected.
  • VEGFR-2 kinase inhibition blocked the DAPT-induced up-regulation of eNOS.

Conclusions:

  • γ-secretase inhibitor DAPT enhances VEGFR-2 and eNOS expression in microvascular endothelial cells.
  • The up-regulation of eNOS is dependent on increased VEGFR-2 expression.
  • Combining γ-secretase inhibitors with eNOS disruption or VEGF signaling interruption may improve anti-angiogenic tumor treatments.

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