Drug-eluting stents releasing antimitotic drugs are frequently used in patients undergoing percutaneous coronary interventions. Although these stents inhibit proliferation of vascular smooth muscle cells and thus reduce rates of early stenosis, they also impair proliferation of endothelial cells. The resulting delayed arterial healing increases the risk of thrombosis and leads to higher late stent restenosis. Optimization of endothelium repair is then necessary to prevent intimal thickening and in-stent restenosis.

Using a mouse model of carotid injury, we previously demonstrated that 17βestradiol (E2) accelerates endothelium regeneration through estrogen receptor ER⍺ but not ERβ (1) and involvement of FGF-2 (2). However, the molecular and cellular mechanisms underlying this beneficial effect still remain poorly understood, mainly due to the lack of appropriate models and tools to visualize endothelium. Here, we employed en face confocal microscopy to follow endothelium repair in longitudinally opened and flattened mouse carotid arteries.

We showed that E2 accelerates both migration and proliferation of endothelial cells and increased the recruitment of cells in an uninjured adjacent retrograde zone, leading to enlarged reendothelialized area (3).

Many studies suggest that circulating bone marrow (BM) derived cells are involved in arterial healing. Thus, we generated chimeric mice by grafting wild type mice with ER⍺ -/- or ER⍺+/+ BM and vice versa. The beneficial effect of E2 was abolished when the ER⍺ was absent either in donor or in receiver mice, demonstrating that both BM and non-BM ER⍺-expressing cells cooperate to mediate E2 regenerative effects. Using a cell-specific inactivation mouse model of ER⍺, by the loxP/Cre recombination system, we showed that endothelial ER⍺ is absolutely required in the accelerative effect of E2 on reendothelialization. To precise which BM derived cells are involved in the E2 effect, the implication of ER⍺-expressing macrophages is now under investigation.

These results might help us to propose new strategy to optimize post-angioplasty and in-stent reendothelialization.

1. Brouchet L., Circulation, 2001.

2. Fontaine V. Am J Pathol, 2006.

3. Filipe C. Am J Physiol Heart Circ Physiol, 2008.