HIF-1α-mediated inhibition of the sFlt-1/sENG/TNF-α pathway promotes angiogenesis to ameliorate pre-eclampsia

Pre-eclampsia (PE) is a common pregnancy complication, closely associated with endothelial dysfunction and inhibition of angiogenesis. This study aims to explore the pathological mechanisms causing endothelial dysfunction and suppressed angiogenesis in PE, with the aim of identifying potential drug targets. Human umbilical vein endothelial cells (HUVECs) were exposed to angiotensin II (Ang-II) to mimic PE-related endothelial dysfunction. Angiogenic capacity was evaluated using tube formation assay, scratch assay, flow cytometry, and CCK-8 assay. A Reduced Uterine Perfusion Pressure (RUPP) mouse model was established to recapitulate PE. Expression profiles of hypoxia-inducible factor-1α (HIF-1α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sENG), and tumor necrosis factor-α (TNF-α) were quantified via Western blot and RT-qPCR. Biochemical assessments included levels of malondialdehyde, superoxide dismutase, glutathione, and the urine protein/creatinine (UP/cr) ratio. Systolic blood pressure was measured while placental histopathology was examined using hematoxylin and eosin (HE) staining. In HUVECs exhibiting endothelial dysfunction, ICAM-1 and VCAM-1 were markedly upregulated, whereas HIF-1α expression was significantly reduced. Overexpression of HIF-1α boosted HUVEC proliferation and migration, attenuated Apoptosis and oxidative stress, enhanced expression of VEGF and PLGF, and suppressed expression of sFlt-1, sENG, and TNF-α, thereby promoting angiogenesis. In the RUPP-modeled PE mouse model, diminished HIF-1α expression coincided with elevated ICAM-1 and VCAM-1, leading to endothelial dysfunction, elevated systolic blood pressure, and increased UP/cr ratio. Conversely, HIF-1α overexpression ameliorated placental tissue damage and oxidative stress, upregulated VEGF and PLGF, downregulated sFlt-1, sENG, TNF-α, ICAM-1, and VCAM-1, and restored angiogenic capacity. HIF-1α ameliorates endothelial dysfunction in PE by suppressing the sFlt-1/sENG/TNF-α signaling pathway, thereby promoting angiogenesis and alleviating PE.

Endothelial dysfunction; Hypoxia inducible factor 1 subunit alpha; Preeclampsia; Pregnancy complications; Vascular regeneration.