Oxidized LDL-induced angiogenesis involves sphingosine-1-phosphate. Prevention by anti-S1P antibody.

British journal of pharmacology

PubMedID: 25176316

Camaré C, Trayssac M, Garmy-Susini B, Mucher E, Sabbadini R, Salvayre R, Negre-Salvayre A. Oxidized LDL-induced angiogenesis involves sphingosine-1-phosphate. Prevention by anti-S1P antibody. Br J Pharmacol. 2014;.
BACKGROUND AND PURPOSE
Neovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial because both angiogenic and anti-angiogenic effects were reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid mediator sphingosine-1-phosphate (S1P) in this proces is not known. Thus, we aimed to investigate whether S1P is implicated in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody could prevent this effect.

EXPERIMENTAL APPROACH
Angiogenesis was assessed by capillary tube formation by Human Microvascular Endothelial Cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice.

KEY RESULTS
Human oxLDL exhibited a biphasic angiogenic effect on HMEC-1, low concentration being angiogenic, higher concentration being cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signaling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentration of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by intraperitoneal injection of the anti-S1P antibody.

CONCLUSION AND IMPLICATIONS
These data emphasize the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and the efficacy of the anti-S1P antibody in blocking the angiogenic effect of oxLDL.