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

Zou,Yu-Hui; Cao,Yi-Qun; Wang,Lai-Xing; Zhang,Yu-Hui; Yue,Zhi-Jian; Liu,Jian-Min

doi:10.3892/etm.2011.257

July-August 2011 Volume 2 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

July-August 2011 Volume 2 Issue 4

Full Size Image

Article

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

Authors:
- Yu-Hui Zou
- Yi-Qun Cao
- Lai-Xing Wang
- Yu-Hui Zhang
- Zhi-Jian Yue
- Jian-Min Liu
View Affiliations / Copyright

Affiliations: Department of Neurosurgery, Changhai Hospital, Shanghai 200433, P.R. China
Pages: 725-729
|
Published online on: April 19, 2011

https://doi.org/10.3892/etm.2011.257
Expand metrics +

Abstract

Although previous studies have shown that γ-secretase inhibitors significantly suppress tumor growth via anti-angiogenesis, the mechanism involved in the regulation of tumor angiogenesis by γ-secretase inhibitors has not been clearly understood. The objective of this study was to investigate the regulation of vascular endothelial growth factor receptor (VEGFR) and endothelial nitric oxide synthase (eNOS) by a γ-secretase inhibitor in the H5V mouse microvascular endothelial cell line. H5V cells were cultured with different concentrations of the γ-secretase inhibitor DAPT for 48 h and with 100 µmol/l DAPT at different incubation times. Protein and mRNA expression of VEGFR-1, VEGFR-2, VEGFR-3 and eNOS was measured by Western blotting and real-time PCR, respectively. The VEGFR-2 kinase inhibitor was used to assess the role of VEGFR-2 in eNOS regulation. We found that the γ-secretase inhibitor DAPT increased protein and mRNA expression of VEGFR-2 and eNOS, but decreased VEGFR-1 expression and had no significant effect on VEGFR-3. Up-regulation of eNOS was blocked by the VEGFR-2 kinase inhibitor. In conclusion, the γ-secretase inhibitor enhances VEGFR-2 and eNOS expression, and the up-regulation of eNOS is dependent on an increase in VEGFR-2. Thus, we suggest that administration of the γ-secretase inhibitor be combined with disruption of eNOS or interruption of VEGF signaling, which may improve the anti-angiogenic efficacy in tumor treatments.

View Figures

View References

1.	Masuda S, Kumano K, Suzuki T, et al: Dual antitumor mechanisms of Notch signaling inhibitor in a T-cell acute lymphoblastic leukemia xenograft model. Cancer Sci. 100:2444–2450. 2009. View Article : Google Scholar : PubMed/NCBI
2.	Caiado F, Real C, Carvalho T and Dias S: Notch pathway modulation on bone marrow-derived vascular precursor cells regulates their angiogenic and wound healing potential. PLoS One. 3:e37522008. View Article : Google Scholar : PubMed/NCBI
3.	Cook KM and Figg WD: Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 60:222–243. 2010. View Article : Google Scholar : PubMed/NCBI
4.	Michel T and Vanhoutte PM: Cellular signaling and NO production. Pflugers Arch. 459:807–816. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Toda N, Ayajiki K and Okamura T: Interaction of endothelial nitric oxide and angiotensin in the circulation. Pharmacol Rev. 59:54–87. 2007. View Article : Google Scholar : PubMed/NCBI
6.	Hirashima M: Regulation of endothelial cell differentiation and arterial specification by VEGF and Notch signaling. Anat Sci Int. 84:95–101. 2009. View Article : Google Scholar : PubMed/NCBI
7.	Shawber CJ, Funahashi Y, Francisco E, et al: Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest. 117:3369–3382. 2007. View Article : Google Scholar : PubMed/NCBI
8.	Kroll J and Waltenberger J: VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun. 252:743–746. 1998. View Article : Google Scholar : PubMed/NCBI
9.	Wang Y, Nagase S and Koyama A: Stimulatory effect of IGF-I and VEGF on eNOS message, protein expression, eNOS phosphorylation and nitric oxide production in rat glomeruli, and the involvement of PI3-K signaling pathway. Nitric Oxide. 10:25–35. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Facemire CS, Nixon AB, Griffiths R, Hurwitz H and Coffman TM: Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression. Hypertension. 54:652–658. 2009. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Related Articles