<p>Vascular endothelial dysfunction plays a central role in the progression of gestational hypertension (GH). A portion of GH cases progress to preeclampsia, suggesting shared angiogenic imbalances and placental dysfunction as underlying mechanisms. Laminin subunit alpha-4 (LAMA4) downregulation has been linked to preeclampsia pathogenesis. This study explored the precise role of LAMA4 in HUVEC dysfunction induced by hypoxia/reoxygenation (H/R) insults. HUVECs were treated with H/R conditions to mimic the in vitro model of GH. LAMA4 mRNA expression was analyzed using quantitative PCR. Protein expression was detected by immunoblotting. The effects on HUVEC dysfunction under H/R were evaluated by measuring cell viability, proliferation, apoptosis, tube formation, and ROS and MDA levels. The relationship between SP1 and LAMA4 was confirmed by chromatin immunoprecipitation (ChIP) and luciferase assays. The interaction between NEDD4 and LAMA4 was confirmed by protein stability analysis and immunoprecipitation (IP) assay. LAMA4 expression was decreased in GH serum and H/R-treated HUVECs. Rescue of LAMA4 expression recovered HUVEC growth and tube formation capacities and diminished cell apoptosis and oxidative stress under H/R insults. Mechanistically, SP1 upregulated LAMA4 by transcriptionally activating its promoter. Furthermore, NEDD4 downregulated LAMA4 expression through ubiquitination. Silencing LAMA4 abrogated the attenuated effects of SP1 upregulation or NEDD4 depletion on HUVEC dysfunction induced by H/R. Our study demonstrates that LAMA4, which is transcriptionally upregulated by SP1 and post-translationally downregulated by NEDD4, mediates H/R-induced dysfunction in HUVECs by modulating cell growth, tube formation, and oxidative stress.</p>