Hypoxia-Driven CA2 Promotes Trophoblast Dysfunction in Preeclampsia

Explore the potential function of Carbonic Anhydrase 2 (CA2) in the pathophysiology of preeclampsia. Peripheral blood and placental samples were collected from healthy pregnant women and patients with preeclampsia. Placental CA2 expression was validated in independent clinical cohorts and experimental mouse models. HTR-8/SVneo cells were cultured and transfected with a CA2 overexpression plasmid to evaluate trophoblast dysfunction. Bulk RNA sequencing was performed to identify downstream genes associated with CA2 overexpression, followed by VEGFA rescue experiments. Hypoxia-related regulation of CA2 was investigated. Lipid nanoparticle (LNP)-encapsulated siRNA against CA2 was constructed in an L-NAME-induced PE model to evaluate therapeutic effects. CA2 expression was significantly increased in placental tissues and maternal serum from women with PE and was also elevated in experimental PE mouse models. CA2 predominantly localized in trophoblast cells, and correlated positively with serum creatinine and urea and correlated negatively with fetal birth weight. CA2 overexpression markedly suppressed trophoblast proliferation, migration, and invasion, without affecting apoptosis. Transcriptomic analysis suggested that vascular endothelial growth factor A (VEGFA) acted as a downstream mediator of CA2, and VEGFA overexpression partially rescued CA2-induced trophoblast dysfunction. CA2 expression was upregulated under hypoxic conditions and regulated by hypoxia-inducible factor-1α (HIF-1α). LNP-mediated CA2 silencing partially improved placental structure and fetal outcomes in vivo. CA2 is upregulated in the preeclamptic placenta and is associated with placental dysfunction and adverse fetal outcomes. Mechanistically, CA2 may act downstream of HIF-1α and contribute to trophoblast dysfunction partly through modulation of VEGFA signaling, and CA2 silencing partially improved maternal and fetal outcomes, highlighting CA2 as a potential therapeutic target for preeclampsia.