A role for soluble HLA‐G1 in the induction of vascular cell apoptosis

Abstract

Uterine spiral artery remodelling is a crucial adaptation in early pregnancy that allows a sufficient blood supply to reach the developing fetus. We have shown that this vascular remodelling involves endothelial and vascular smooth muscle cell apoptosis triggered by the fetal-derived trophoblast cells. Extravillous trophoblasts produce soluble HLA-G1. We have investigated the hypothesis that soluble HLA-G1 is an important regulator of vascular cell apoptosis. Endothelial cells (primary HUVEC or a cell line, SGHEC-7), vascular smooth muscle cells (human aortic SMC line) or extravillous trophoblasts were incubated with recombinant sHLA-G1 and apoptosis was monitored by time-lapse microscopy and western blot analysis of apoptotic markers. Soluble HLA-G1 induced apoptotic morphological changes in endothelial cells. Apoptosis was confirmed using the broad-spectrum caspase inhibitor zVAD-fmk, which abrogated sHLA-G1 induced cell death. In addition, western blot analysis showed that sHLA-G1 treated endothelial cells had increased production of the apoptotic marker cleaved PARP. Soluble HLA-G1-induced endothelial apoptosis was almost completely blocked in the presence of an antibody that prevents Fas/FasL interactions. Soluble HLA-G1 also induced vascular smooth muscle cell apoptosis but had no effect on trophoblast cell survival. In conclusion, we have shown that sHLA-G1 induces vascular cell apoptosis and that for endothelial cells this effect may be partly through the Fas/FasL system. Soluble HLA-G1 may therefore have a role in the induction of uterine spiral artery remodelling seen in early pregnancy.