Published online before print July 8, 2004, doi: 10.1161/01.RES.0000138300.41642.15
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Submitted on January 5, 2004
Revised on June 25, 2004
Accepted on June 25, 2004
Thromboxane A2 Receptor Signaling Inhibits Vascular Endothelial Growth Factor-Induced Endothelial Cell Differentiation and Migration
Anthony W. Ashton * and J. Anthony Ware
From the Departments of Medicine (Cardiology) and Molecular Pharmacology, the Albert Einstein College of Medicine, Yeshiva University, Bronx, NY.
* To whom correspondence should be addressed. E-mail: ashton{at}aecom.yu.edu.
Vascular endothelial growth factor (VEGF) is an important patho-physiological mediator of angiogenesis. VEGF-induced endothelial cell (EC) migration and angiogenesis often occur in complicated environments containing multiple agents capable of modifying the response. Thromboxane (TX) A2 is released from multiple cell types and is a prime mediator of pathogenesis of many vascular diseases. Human EC express both TXA2 receptor (TP) isoforms; however, the effects of individual TP isoforms on VEGF-induced EC migration and angogenesis are unknown. We report here that the TXA2 mimetic [1S-(1
, 2
(5Z), 3(1E, 3R), 4]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxab icyclo-[2.2.1]heptan-2yl]-5'-heptenoic acid (IBOP) (100 nM) is a potent antagonist (IC50 30 nM) of VEGF-induced EC migration and differentiation. TP, but not TP, expression is required for the inhibition of VEGF-induced migration and angiogenesis. IBOP costimulation suppressed nitric oxide (NO) release from VEGF-treated EC through decreased activation of Akt, eNOS, and PDK1. TP costimulation also ablated the increase in focal adhesion formation in response to VEGF. This mechanism was characterized by decreased recruitment of focal adhesion kinase (FAK) and vinculin to the v3 integrin and reduced FAK and Src activation in response to VEGF. Addition of NO donors together with transfection of a constitutively active Src construct could circumvent the blockade of VEGF-induced migration by TP; however, neither intervention alone was sufficient. Thus, TP stimulation appears to limit angiogenesis, at least in part, by inhibiting the pro-angiogenic cytokine VEGF. These data further support a role for antagonism of TP activation in enhancing the angiogenic response in tissues exposed to elevated TXA2 levels in which revascularization is important.
Key words: thromboxane • vascular endothelial growth factor • migration • focal adhesions
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