Metformin diminishes lipopolysaccharide-induced endotoxemia and cardiopulmonary microvascular coagulopathy: Molecular insights on vascular endothelial growth factor-A and its receptors.

Vascular endothelial growth factor (VEGF)-A, a hypoxia- and cytokine-inducible biomarker of endothelial activation, together with its receptors VEGFR1 and VEGFR2, contributes to endotoxemia and early sepsis-related vascular dysfunction by increasing permeability and tissue edema. The current research explored the dose-dependent therapeutic effects of metformin on lipopolysaccharide (LPS)-induced endotoxemia with cardiopulmonary dysfunction and microvascular coagulopathy in male Wistar rats. Endotoxemia was induced by a single intraperitoneal LPS injection, and metformin was administered at 50, 100, 200, or 400 mg/kg. Metformin dose-dependently improved survival and attenuated LPS-induced tachycardia, QTc prolongation, ST-segment elevation, coagulopathy, hyperglycemia, and elevations in serum cardiac troponin I (cTnI), ferritin, and lactate dehydrogenase (LDH). Histopathological and immunohistochemical analyses showed reduced VEGF-A, VEGFR1, and VEGFR2 expression in cardiopulmonary tissues, with the 400 mg/kg dose nearly restoring normal levels. KEGG and Reactome analyses revealed that VEGFR2 activation drives PI3K-Akt-eNOS, p38/HSP27, and MAPK/ERK pathways promoting endothelial permeability, inflammation, and coagulopathy. Molecular docking further confirmed potential interactions between metformin and key VEGF signaling proteins-VEGFR2, MAPK1, PDK1, and Src kinase-through hydrogen bonding and hydrophobic contacts, supporting the predicted inhibitory mechanism. STRING protein-protein interaction analysis identified VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4) as central hubs linking angiogenic and adaptor proteins. Collectively, these experimental and computational findings indicate that metformin ameliorates LPS-induced endotoxemia and cardiopulmonary microvascular coagulopathy via modulation of VEGF-A/VEGFR1/VEGFR2 signaling, providing mechanistic and translational insight into its potential endothelial-protective effects especially in comorbid patients on metformin maintenance therapy.