Abstract

Septic encephalopathy results from the intense reaction of the immune system to infection. The role of growth hormone (GH) signaling in maintaining brain function is well established; however, the involvement of the vascular endothelial growth factor receptor-2 (VEGFR2) in the potential modulatory effect of GH on septic encephalopathy-associated endoplasmic reticulum stress (ERS) and blood–brain barrier (BBB) permeability is not well-understood. Therefore, after the induction of mid-grade sepsis by cecal ligation/perforation, rats were subcutaneously injected with recombinant human GH (rhGH)/somatropin alone or preceded by the VEGFR2 antagonist WAG-4S for 7 days. rhGH/somatropin reduced bodyweight loss and plasma endotoxin, maintained the hyperthermic state, and improved motor/memory functions. Additionally, rhGH/somatropin increased the junctional E-cadherin and β-catenin pool in the cerebral cortex to enhance the BBB competency, effects that were abolished by VEGFR2 blockade. Also, it activated cortical VEGFR2/mammalian target of the Rapamycin (mTOR) axis to mitigate ERS. The latter was reflected by the deactivation of the inositol-requiring enzyme-1α (IRE1α)/spliced X-box binding protein-1 (XBP1s) trajectory and the reduction in the protein levels of the death markers, C/EBP homologous protein (CHOP)/growth arrest and DNA damage-153 (GADD153), c-jun-N-terminal kinase (JNK), and caspase-3 with the simultaneous augmentation of expression of the unfolded protein response transducer protein kinase R-like ER kinase (PERK). Furthermore, rhGH/somatropin suppressed the phosphorylation of eukaryotic initiation factor-2α (eIF2α), upregulated the gene expression of activating transcription factor-4 (ATF4), GADD34, and glucose-regulated protein-78/binding immunoglobulin (GRP78/Bip). Moreover, it increased the glutathione level and reduced lipid peroxidation in the cerebral cortex. The VEGFR2 antagonist reversed the effect of rhGH/somatropin on PERK and IRE1α and boosted the apoptotic markers but neither affected p-eIF2α nor GADD34. Hence, we conclude that VEGFR2 activation by rhGH/somatropin plays a crucial role in assembling the BBB adherens junctions via its antioxidant capacity, ERS relief, and reducing endotoxemia in septic encephalopathy.

Keywords

Recombinant human growth hormoneSomatropinEndoplasmic reticulum stressUnfolded protein responseBlood–brain barrierVascular endothelial growth factor receptor-2