Activation of the Thromboxane A2 Receptor by 8-Isoprostane Inhibits the Pro-Angiogenic Effect of Vascular Endothelial Growth Factor in Scleroderma.
The pathogenesis of scleroderma (SSc) includes components of autoimmunity, vascular dysfunction, and accumulation of extracellular matrix. 8-isoprostane, an oxidized lipid created by oxidative stress, activates the thromboxane A2 receptor (TXAR) and the Rho-associated kinase (ROCK) pathway. In this study, we determined whether the TXAR was activated by 8-isoprostane in SSc endothelial cells (ECs) and whether this pathway inhibited VEGF-induced angiogenesis. Elevated 8-isoprostane was observed in plasma and conditioned media from SSc patients. SSc-conditioned media inhibited EC tube formation, whereas addition of vitamin E, by reducing 8-isoprostane, increased tube formation. VEGF did not induce angiogenesis in SSc ECs, but vitamin E or TXAR inhibition restored its effect. The expression of TXAR, RhoA, and ROCK1/2 was elevated in SSc ECs. ROCK activity and 8-isoprostane-induced ROCK activation were significantly higher in SSc ECs, whereas VEGF had no effect. The hyper-activation of the TXAR leads to inhibition of VEGF-induced angiogenesis, as inhibition of the TXAR pathway results in a blockade of 8-isoprostane-induced ROCK activation and restoration of VEGF activity. These results suggest that the TXAR pathway has a crucial role in angiogenesis and that 8-isoprostane is not just a by-product of oxidative stress but also has a significant role in the impaired angiogenesis that characterizes SSc.
Department of Internal Medicine, Division of Rheumatology, University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA; Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address: ptsou@med.umich.edu.
Pei-Suen
PS
Tsou
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
M Asif
MA
Amin
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phillip L
PL
Campbell
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
George
G
Zakhem
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Beatrix
B
Balogh
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Gautam
G
Edhayan
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Ray A
RA
Ohara
Department of Internal Medicine, Division of Rheumatology, University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA; Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Elena
E
Schiopu
Department of Internal Medicine, Division of Rheumatology, University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA; Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Dinesh
D
Khanna
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA; VA Medical Service, Ann Arbor, Michigan, USA.
Alisa E
AE
Koch
Department of Internal Medicine, Division of Rheumatology, University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA; Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
David A
DA
Fox
D000328:Adult; D003094:Collagen; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004338:Drug Combinations; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D007797:Laminin; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D010766:Phosphorylation; D011509:Proteoglycans; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects / Q000502:physiology*; D012595:Scleroderma, Systemic / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000502:physiology
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; C075750:8-epi-prostaglandin F2alpha; D003094:Collagen; D015237:Dinoprost; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054460:rho-Associated Kinases