Objectives: Preeclampsia (PE) is a serious disorder of human pregnancy; it can be categorised into subtypes of early-onset PE (EPE, occurring before 34 weeks of gestation) and late-onset PE (LPE, occurring after 34 weeks of gestation). EPE is often severe and associated with intrauterine growth restriction (IUGR). Circulating endothelial progenitor cells (EPCs) play an important role in endothelial cell regeneration, yet these cells are reported to be lower in patients with EPE, suggesting that the endothelial repair mechanisms are compromised in EPE. However, the underlying mechanisms of this disease are not well understood. We have previously reported that high temperature requirement factor A4 (HtrA4) is specifically expressed by the placenta and is significantly up-regulated in EPE. We have also demonstrated that HtrA4 at high levels disrupts endothelial angiogenesis and induces the release of pro- inflammatory factors.
Methods: We examined the effect of HtrA4 on proliferation of human umbilical vein endothelial cells (HUVECs) and primary EPCs isolated from umbilical cord blood of pregnant women. We also examined whether HtrA4 can inhibit EPC differentiation into mature endothelial cells.
Results: We found that high levels of HtrA4 observed in EPE serum inhibited the proliferation of HUVECs. At the molecular level, HtrA4 significantly down-regulated a number of genes that promote cell cycle progression and up-regulated genes that are involved in cell senescence. Furthermore, high levels of HtrA4 also inhibited the proliferation of primary EPCs and prevented EPC differentiation into mature endothelial cells.
Conclusion: High levels of HtrA4 in the maternal circulation may not only damage the endothelium, but also inhibit endothelial cell proliferation and induces these cells to senesce prematurely. Furthermore, high blood levels of HtrA4 may also inhibit the proliferation and differentiation of circulating EPCs and therefore preventing the cellular repair of damaged/aging endothelium.