Semaphorin 3A disrupts endothelial structure and lysosomal function: <i>in vitro</i> mechanisms and <i>in vivo</i> evidence in hypertensive pregnancy

Semaphorin 3A (SEMA3A), a neurovascular guidance molecule, is increasingly recognized for its roles in angiogenesis and immune regulation, yet its impact on vascular dysfunction during pregnancy remains uncertain. We examined circulating and placental SEMA3A levels in women with healthy pregnancies, those with hypertensive disorders of pregnancy with appropriate-for-gestational-age fetuses, and hypertensive pregnancies complicated by fetal growth restriction, supplementing these analyses with in vitro endothelial assays. In maternal plasma and placental tissues, SEMA3A levels were elevated in hypertensive pregnancies, peaking in cases with fetal growth restriction. In cultured endothelial cells, SEMA3A disrupted cytoskeletal organization, compromised barrier stability, and altered cellular morphology. These changes were linked to lysosomal accumulation of its receptor neuropilin-1 and altered lysosomal function. Collectively, these findings identify SEMA3A as a regulator of endothelial cytoskeletal and lysosomal dynamics. By connecting in vitro mechanistic studies with in vivo pregnancy samples, this work underscores a novel role for SEMA3A that may be pertinent to hypertensive pregnancy and its complications.