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Blood. 2002 Mar 1;99(5):1646-50.

Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells.

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Department of Medicine and Kaplan Cancer Center, New York University Medical School, New York, NY 10016, USA.


Angiogenesis is required for tumor growth and metastasis. It has recently been suggested that thrombin is a potent promoter of angiogenesis. We therefore examined the possibility that thrombin could be inducing the expression of angiopoietin-2 (Ang-2), necessary for remodeling. Human umbilical vein endothelial cells were incubated with or without thrombin (1 U/mL) for 1 to 24 hours and then examined for messenger RNA (mRNA) by Northern analysis. Enhanced mRNA expression (about 4-fold over baseline) was noted at 4 hours. Enhanced expression of Ang-2 mRNA was secondary to enhanced transcription (about 4-fold), with no effect on stabilization. Enhanced Ang-2 mRNA transcription was inhibited by H7 and PD98059, indicating the requirement of serine/threonine kinases as well as the mitogen-activated protein kinase pathway. Up-regulation of mRNA was associated with enhanced Ang-2 protein synthesis and secretion as assayed by immunoblot. Thrombin-induced secreted Ang-2 inhibited the binding of recombinant (35)S-Ang-1 to its Tie-2-Fc receptor, demonstrating functionality. Hirudin reversed this effect, demonstrating thrombin specificity. Thus, thrombin-induced tumorigenesis and metastasis is associated with enhanced Ang-2 protein synthesis and secretion via enhanced transcription of Ang-2. This could help explain how thrombin promotes angiogenesis.

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