High levels of HtrA4 detected in preeclamptic circulation may disrupt endothelial cell function by cleaving the main VEGFA receptor KDR

Abstract

Systemic endothelial dysfunction is a key characteristic of preeclampsia (PE), which is a serious disorder of human pregnancy. We have previously reported that high‐temperature requirement factor (Htr)A4 is a placenta‐specific protease that is secreted into the maternal circulation and significantly up‐regulated in PE, especially early‐onset PE. We have also demonstrated that high levels of HtrA4 detected in the early onset PE circulation induce endothelial dysfunction in HUVECs. In the current study, we investigated whether HtrA4 could cleave the main receptor of VEGFA, the kinase domain receptor (KDR), thereby inhibiting VEGFA signaling. We first demonstrated that HtrA4 cleaved recombinant KDR in vitro. We then confirmed that HtrA4 reduced the level of KDR in HUVECs and inhibited the VEGFA‐induced phosphorylation of Akt kinase, which is essential for downstream signaling. Further functional studies demonstrated that HtrA4 prevented the VEGFA‐induced tube formation in HUVECs and dose‐dependently inhibited the VEGFA‐induced angiogenesis in explants of mouse aortic rings. These data strongly suggest that high levels of HtrA4 in the maternal circulation could cleave the main receptor of VEGFA in endothelial cells to induce a wide‐spread impairment of angiogenesis. Our studies therefore suggest that HtrA4 is a potential causal factor of early onset PE.—Wang, Y., La, M., Pham, T., Lovrecz, G. O., Nie, G. High levels of HtrA4 detected in preeclamptic circulation may disrupt endothelial cell function by cleaving the main VEGFA receptor KDR. FASEB J. 33, 5058–5066 (2019). http://www.fasebj.org

HtrA4 is up-regulated during trophoblast syncytialization and BeWo cells fail to syncytialize without HtrA4

“…Likewise, HtrA4 protein in the maternal serum is significantly elevated in early-onset preeclampsia [21][22][23] . Our studies further suggest that elevated circulating HtrA4 can adversely affect the integrity and function of maternal vascular endothelium and may play a role in the pathogenesis of preeclampsia [24][25][26][27][28] .…”

“…Likewise, HtrA4 protein in the maternal serum is significantly elevated in early-onset preeclampsia [21][22][23] . Our studies further suggest that elevated circulating HtrA4 can adversely affect the integrity and function of maternal vascular endothelium and may play a role in the pathogenesis of preeclampsia [24][25][26][27][28] .However, to date, the normal function of HtrA4 in the human placenta is unknown. Since HtrA4 is expressed in cytotrophoblasts and syncytiotrophoblasts 22,23 , this study aimed to investigate the functional role of HtrA4 in trophoblast syncytialization.…”

HtrA4 Protease Promotes Chemotherapeutic-Dependent Cancer Cell Death

“…Our finding that HtrA4 can be an important factor that regulates the motility of cells is in agreement with the study of Liu et al (2018), who showed that ectopic expression of HtrA4 significantly decreased trophoblast cell migration [20]. The involvement of HtrA4 in the regulation of cell cycle genes in umbilical vein endothelial cells was also observed [26].…”

“…Moreover, it was indicated that the allelic ratio of HtrA4 is lower in glioblastoma compared to normal DNA control [25]. Recently, the correlation of HtrA4 with cell proliferation and cell cycle modulation was demonstrated [26]. In spite of HtrA4 involvement in important physiological, pathological, and cellular processes, its function in the cell is poorly understood.…”

SUMO2/3 participates in regulating the protective effect of propofol on human umbilical vein endothelial cells

“…The vascular wall is covered by a layer of endothelial cells, which is an important barrier between blood vessels and tissues [4]. When vascular injury occurs, the function of vascular endothelial cells is disordered or even damaged, which leads to the direct entry of inflammatory cells and molecules into tissues, aggravating the injury of tissue cells [5,6]. Therefore, it is of great clinical value to study the molecular mechanism of I/R injury of vascular endothelial cells.…”