Elevated protease HtrA4 in the maternal circulation of preeclampsia may contribute to endothelial barrier disruption by cleaving key junctional protein VE-cadherin.

Preeclampsia is hallmarked by systemic endothelial dysfunction, including increased endothelial permeability and oedema. Placenta-derived factors in maternal blood contribute to endothelial barrier impairment, but molecular mechanisms are unclear. HtrA4 is a placenta-specific protease that is secreted into the maternal circulation and elevated in early-onset preeclampsia. In this study, we found HtrA4 cleaved the key endothelial junctional protein VE-cadherin in vitro. HtrA4 at concentrations found in preeclampsia also cleaved VE-cadherin in HUVECs as an endothelial model, disrupted cell-cell connections and induced intercellular gaps. These results provide critical insights into understanding the molecular mechanisms of endothelial barrier disruption in preeclampsia.