PLoS One. 2026 Oct 28;21(10):e0359834. doi: 10.1371/journal.pone.0359834. eCollection 2026.
ABSTRACT
BACKGROUND: Endothelial dysfunction is a central contributor to the development of diabetic foot complications. However, the regulatory mechanisms underlying impaired vascular endothelial cell (VEC) function in diabetic foot remain incompletely understood. Transient Receptor Potential Melastatin 7 (TRPM7) is implicated in cardiovascular pathology, yet its role in diabetic foot-related endothelial impairment is unclear.
METHODS: Primary VECs were isolated from foot vascular tissues obtained from control participants and patients with DFUs and identified by CD31 and factor VIII immunofluorescence. Proliferation, apoptosis, migration, and in vitro tube formation were quantitatively assessed. TRPM7 was overexpressed in control-derived VECs and knocked down using shRNA in DFU-derived VECs. TRPM7 expression and VEGFA-AKT-ERK-related proteins were evaluated using RT-qPCR and Western blotting. Advanced glycation end products (AGEs) and inducible nitric oxide synthase (iNOS) concentrations in conditioned culture supernatants were measured by ELISA.
RESULTS: Compared with control-derived VECs, DFU-derived VECs exhibited reduced proliferation, migration, and tube formation, together with increased apoptosis and elevated conditioned-supernatant AGE and iNOS protein concentrations. TRPM7 expression was higher in DFU-derived VECs. TRPM7 overexpression in control-derived VECs induced a dysfunctional cellular phenotype, whereas TRPM7 knockdown in DFU-derived VECs partially restored proliferation, migration, and tube formation and reduced apoptosis. TRPM7 manipulation was also accompanied by changes in VEGFA expression and AKT and ERK phosphorylation, indicating an association between TRPM7 status and dysregulated VEGFA-AKT-ERK-related signaling.
CONCLUSION: In primary human VEC cultures, increased TRPM7 expression was associated with impaired endothelial proliferation, migration, and tube formation and with altered VEGFA-related AKT/ERK signaling. This supporting TRPM7 as a candidate regulator of endothelial dysfunction under diabetic-foot-related conditions.
PMID:42949898 | DOI:10.1371/journal.pone.0359834