Placental expression of aminopeptidase-Q (laeverin) and its role in the pathophysiology of preeclampsia.

OBJECTIVE

The purpose of this study was to investigate the expression and subcellular localization of laeverin, a placenta-specific membrane-bound aminopeptidase, in preeclamptic placentas and its role in trophoblast cell migration and invasion.

STUDY DESIGN

Expression of laeverin was investigated in 6 normal and 6 preeclamptic placentas with the use of immunofluorescence, sodium dodecylsulfate-polyacrylamide gel electrophoresis with Western blot analysis and immunoelectron microscopy. The role of laeverin in trophoblast migration and invasion was studied with the use of the xCelligence system and Boyden chambers with Matrigel in HTR-8/SVneo cells. The effect of laeverin gene-silencing on selected genes that are involved in cell transformation and tumorigenesis was evaluated by polymerase chain reaction array. The Student t test, Mann-Whitney U test, χ(2) test, or F-test was used to compare groups as appropriate.

RESULTS

Laeverin was expressed in the cell membrane of villous trophoblasts in third-trimester healthy placentas; in preeclamptic placentas, it was expressed ectopically in the cytoplasm, especially in microvesicles. Immunoelectron microscopy showed laeverin leakage into the fetal capillaries and abundant expression in microvesicles in preeclamptic placentas. Migration and invasion of HTR-8/SVneo cells were reduced by 11.5% (P = .023) and 56.7% (P = .001), respectively, by laeverin gene-silencing. Analysis of downstream pathways affected by laeverin-silencing demonstrated significant down-regulation of integrin A2 (39-fold), integrin B3 (5-fold), and matrix metalloprotease 1 (36-fold).

CONCLUSION

Expression of laeverin protein is altered in preeclamptic placentas. Its ectopic expression in the cytoplasm and microvesicles, rather than the cell membrane and leakage into the fetal capillaries, may have a role in the pathophysiologic condition of preeclampsia. Laeverin gene appears to be involved in trophoblast cell migration and invasion through interaction with integrins and matrix metalloprotease 1.