Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women

impaired invasion of uteroplacental arteries by extravillous trophoblast ce lls is a key pathogenic mechanism of preeclampsia. We previously demonstrat ed that reduced trophoblast invasion into uteroplacental spiral arteries wa s associated with an excess of macrophages in and around these arteries. To explore the significance of these observations, we correlated the extent o f extravillous trophoblast apoptosis in placental bed biopsy specimens with macrophage distribution and studied the effect of macrophages upon trophob last apoptosis in vitro. Extravillous trophoblast hybrid cells were cocultu red with activated macrophages exposed to exogenous tumor necrosis factor a lpha (TNF alpha), anti-tumor necrosis factor receptor I (TNF-RI), and trypt ophan depletion, and the rates of trophoblast apoptosis were measured. Extr avillous trophoblast hybrid cells showed increased rates of apoptosis follo wing exposure to exogenous TNF alpha, with tryptophan depletion, and when c ocultured with activated macrophages. The proapoptotic effects of macrophag es; in vitro were completely inhibited only by simultaneous addition of try ptophan and anti-TNF-RI. Our data indicate that macrophages, residing in ex cess in the placental bed of preeclamptic women, are able to limit extravil lous trophoblast invasion of spiral arterial segments through apoptosis med iated by the combination of TNF alpha secretion and tryptophan depletion. T he mechanisms by which macrophages are activated and recruited to the place ntal bed are presently unknown but are likely central to the pathogenesis o f preeclampsia.