Editors' ChoiceAngiogenesis

The Toll of Stress on Vessels

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Science Signaling  26 Oct 2010:
Vol. 3, Issue 145, pp. ec328
DOI: 10.1126/scisignal.3145ec328

The link between inflammation and angiogenesis is well established; inflammatory cells produce factors, such as vascular endothelial growth factor (VEGF), that promote neovascularization, and new endothelial cells can recruit inflammatory cells, which promote inflammation. Noting that less is known about how inflammation-induced oxidation products might modulate angiogenesis, West et al. investigated the effects of naturally occurring oxidation products of lipids, including ω-(2-carboxyethyl)pyrrole (CEP) and other pyrroles, on blood vessel growth and wound healing. The concentration of CEP was increased in mice early during wound healing and decreased when the wound was healed. In contrast, concentrations of CEP remained increased in highly vascularized tumors in human and mouse melanoma. CEP had pro-angiogenic effects on cultured mouse and human endothelial cells (ECs), which did not involve phosphorylation (and activation) of the VEGF receptor. Inhibitors of VEGF signaling had no effect on CEP-induced vascularization in a wound-healing assay. Stimulation of EC angiogenesis by CEP and other pyrroles was also not affected by deletion of scavenger receptors, which can bind and internalize lipid products. Instead, deletion of Toll-like receptor 2 (TLR2), but not TLR4, prevented CEP-induced vascularization of ECs. Pam3CSK4, a ligand for TLR2, stimulated angiogenesis from aortic rings of TLR2+/+, but not TLR2–/–, mice. Inhibition of VEGF signaling in the context of TLR2 deletion had an additive effect on the inhibition of wound healing in mice. Administration of CEP to mice with ischemic injury promoted revascularization compared with that in untreated mice, whereas CEP had no effect on wound healing in TLR2–/– mice. In addition, antibodies against CEP led to diminished wound healing in injured mice. Together, these data suggest that TLR2 can sense and respond to endogenous products of lipid oxidation to promote angiogenesis in the context of inflammation.

X. Z. West, N. L. Malinin, A. A. Merkulova, M. Tischenko, B. A. Kerr, E. C. Borden, E. A. Podrez, R. G. Salomon, T. V. Byzova, Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467, 972–976 (2010). [PubMed]