The role of FPR2/ALX in the vascular wall

Abstract

Cardiovascular diseases caused by atherosclerosis are a leading cause of mortality worldwide. Inflammation has been described as a key component in the development of atherosclerosis. Lipoxin A4 (LXA4) is a lipid mediator derived from arachidonic acid, which has anti-inflammatory and pro-resolution properties mediated through the FPR2/ALX receptor. This receptor is however, not specific to LXA4 and can transduce pro-inflammation or pro-resolution effects depending on the different ligands present in the atherosclerotic milieu.

The aim of the present thesis was to unravel the role of FPR2/ALX signaling in the atherosclerotic vascular wall. In addition, the effects of LXA4 were examined with 2 goals: to assess the use of LXA4 as possible therapeutic option in mouse models of atherosclerosis, and to elucidate if LXA4 effects were mediated through FPR2/ALX signaling. To this end, in vivo, in vitro and ex vivo experiments were used to evaluate the role of the FPR2/ALX receptor in human samples of atherosclerosis and in mice either expressing or lacking the murine homologue of the FPR2/ALX receptor (Fpr2).

It was discovered that macrophages, smooth muscle cells and endothelial cells in human atherosclerotic lesions expressed FPR2/ALX and it was up-regulated by pro-inflammatory stimuli in human monocytes in vitro. In three different mouse models, Fpr2 deletion resulted in decreased atherosclerosis. Macrophages derived from Fpr2 knock-out mice exhibited reduced inflammation and Fpr2 knock-out mice exhibited endothelial dysfunction.

Finally, treatment with the aspirin-triggered LXA4 (ATL, a LXA4 analogue) significantly reduced atherosclerosis, smooth muscle cell migration in vitro and intimal hyperplasia after carotid ligation in vivo. Since this effect was absent in Fpr2 knock-out mice, it supports that Fpr2 transduces anti-inflammatory signaling in response to this lipid mediator.

In summary, the results of the present thesis suggest a dual role for FPR2/ALX signaling in atherosclerosis, with pro-inflammatory property as the disease develops; whereas antiinflammatory signaling was induced by LXA4. In addition, it was discovered that Fpr2 signaling induced differential effects on different cell types within the atherosclerotic lesion.

In conclusion, FPR2/ALX signaling is present in major cells of the vascular wall and is crucial for atherosclerosis development. LXA4 is signaling through FPR2/ALX and this supports the use of LXA4 as a therapeutic option in atherosclerosis as well as restenosis.