The chemokine receptor CX3CR1 coordinates monocyte recruitment and endothelial regeneration after arterial injury

Abstract

Regeneration of arterial endothelium after injury is critical for the maintenance of normal blood flow, cell trafficking, and vascular function. Using mouse models of carotid injury, we show that the transition from a static to a dynamic phase of endothelial regeneration is marked by a strong increase in endothelial proliferation, which is accompanied by induction of the chemokine CX₃CL1 in endothelial cells near the wound edge, leading to progressive recruitment of Ly6C^lo monocytes expressing high levels of the cognate CX₃CR1 chemokine receptor. In Cx3cr1-deficient mice recruitment of Ly6C^lo monocytes, endothelial proliferation and regeneration of the endothelial monolayer after carotid injury are impaired, which is rescued by acute transfer of normal Ly6C^lo monocytes. Furthermore, human non-classical monocytes induce proliferation of endothelial cells in co-culture experiments in a VEGFA-dependent manner, and monocyte transfer following carotid injury promotes endothelial wound closure in a hybrid mouse model in vivo Thus, CX₃CR1 coordinates recruitment of specific monocyte subsets to sites of endothelial regeneration, which promote endothelial proliferation and arterial regeneration.

Keywords: CX3CR1; endothelial cells; monocytes; regeneration; vascular injury.