+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells



Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells



Journal of Cellular Physiology 169(3): 522-531



The coordinate induction of protease activities and cell migration is a principal feature of endothelial cells (ECs) invading the interstitial space in the initial step of angiogenesis. However, the molecular mechanisms of these events are not fully characterized. Ets-1 is a member of the ets gene family of transcription factors, which binds to the Ets binding motif in the cis-acting elements and regulates the expression of certain genes. Four typical angiogenic growth factors, aFGF, bFGF, VEGF, and EGF, induced the expression of ets-1 mRNA in either human umbilical vein endothelial cells (HUVECs), ECV-304 cells (immortalized HUVECs), or human omental microvascular endothelial cells (HOMECs). The expression of ets-1 reached its maximum at 2 hr after factor addition and then decreased to the basal level by 12 hr. For characterization of the role of Ets-1 in angiogenesis, ets-1 antisense and sense oligodeoxynucleotides (ODNs) were constructed. The ets-1 antisense ODN but not sense ODN efficiently blocked the synthesis of Ets-1 protein by human ECs in response to angiogenic growth factors. Moreover, the ets-1 antisense ODN but not sense ODN almost completely abolished the binding of endothelial cell extract to DNA containing the Ets binding motif. The expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of ECs in response to growth factors were significantly inhibited by ets-1 antisense ODN but not by sense ODN. Tube formation by HOMECs in type 1 collagen gel stimulated with EGF was abrogated by ets-1 antisense ODN. Finally, the expression of Ets-1 protein in ECs during angiogenesis in vivo was confirmed by an immunohistochemical analysis using a murine angiogenesis model. These results indicate that the induction of ets-1 mRNA is a mutual phenomenon in ECs stimulated with angiogenic growth factors. Ets-1 appears to play an important role in angiogenesis, regulating the expression of proteases and the migration of ECs.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 008629522

Download citation: RISBibTeXText

PMID: 8952701

DOI: 10.1002/(sici)1097-4652(199612)169:3<522::aid-jcp12>3.0.co;2-7


Related references

Vascular origin determines plasminogen activator expression in human endothelial cells. Renal endothelial cells produce large amounts of single chain urokinase type plasminogen activator. Journal of Biological Chemistry 264(5): 2846-2852, 1989

Pro-urokinase up-regulates the expression of urokinase-type plasminogen activator (u-PA) in human pulmonary arterial endothelial cells. Thrombosis Research 121(4): 485-491, 2008

Differential expression of plasminogen activator inhibitor-1 , urokinase-type plasminogen activator and matrix metalloproteinase-2 in mesangioproliferative glomerulonephritis in rats. Journal of the American Society of Nephrology 7(9): 1743, 1996

A novel mechanism for paracrine stimulation of endometrial angiogenesis Urokinase plasminogen activator /plasminogen activator inhibitor-1 complex, released from stromal cells stimulated with TGF-beta-1, stimulates endothelial cells migration. Fibrinolysis 10(Suppl. 3): 117, 1996

A new synthetic matrix metalloproteinase inhibitor modulates both angiogenesis and urokinase type plasminogen activator activity. Angiogenesis 2(4): 319-329, 1998

Transforming growth factor-beta differently regulates urokinase type plasminogen activator and matrix metalloproteinase-9 expression in mouse macrophages; analysis of intracellular signal transduction. Cell Biology International 39(5): 619-628, 2015

Osteoblasts modulate secretion of urokinase-type plasminogen activator and matrix metalloproteinase-9 in human prostate cancer cells promoting migration and matrigel invasion. Oncology Research 11(1): 17-31, 1999

Urokinase-type plasminogen activator up-regulates its own expression by endothelial cells and monocytes via the u-PAR pathway. Thrombosis Research 103(3): 221-232, 2001

Specific interference of urokinase-type plasminogen activator receptor and matrix metalloproteinase-9 gene expression induced by double-stranded RNA results in decreased invasion, tumor growth, and angiogenesis in gliomas. Journal of Biological Chemistry 280(23): 21882-21892, 2005

(±)Equol inhibits invasion in prostate cancer DU145 cells possibly via down-regulation of matrix metalloproteinase-9, matrix metalloproteinase-2 and urokinase-type plasminogen activator by antioxidant activity. Journal of Clinical Biochemistry and Nutrition 51(1): 61-67, 2012

Urokinase-type plasminogen activator induces BV-2 microglial cell migration through activation of matrix metalloproteinase-9. Neurochemical Research 35(7): 976-985, 2010

Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer. Molecular and Cellular Biochemistry 343(1-2): 163-171, 2010

Significance in gene expression of matrix metalloproteinase-9, urokinase-type plasminogen activator and tissue inhibitor of metalloproteinase for metastases of gastric and/or colo-rectal cancer. Gan to Kagaku Ryoho. Cancer and ChemoTherapy 24(Suppl. 2): 324-331, 1997

Extracellular matrix metalloproteinase inducer up-regulates the urokinase-type plasminogen activator system promoting tumor cell invasion. Cancer Research 67(1): 9, 2007

Effects of hypoxia and reoxygenation on the expression levels of the urokinase-type plasminogen activator, its inhibitor plasminogen activator inhibitor type-1 and the urokinase-type plasminogen activator receptor in human head and neck tumour cells. Oncology Reports 17(5): 1259-1268, 2007