Concomitant Down-Regulation of Et1-Etb System and VEGF Angiogenic Signaling in the Frontal Cortex of Endotoximic Mice: A Heightened Vulnerability to Cerebral Microcirculation in Sepsis

Abstract

Aims: Sepsis is a disease that involves abnormal alterations in the microcirculation, with endothelial dysfunction playing a central role in the pathogenesis and mortality. The exact pathophysiology of brain dysfunction associated with sepsis remains poorly understood and experimental data are scarce. It is likely that cerebral microcirculatory alterations may play a potential role. Thus, the present study sought to investigate whether key angiogenic pathways are altered in the frontal cortexin a clinically-relevant animal model of endotoxemia/sepsis, and verify whether the alterations in angiogenic pathways affect the cerebral capillary density.Main methods: Male mice at 8 weeks of age were administered either with saline alone (control group) or 20 mg/kg lipopolysaccharide (LPS) (treatment group) at different time points (1, 3, 6, and 10 h). Microvascular alterations were determined by measuring levels of cerebral mRNA, protein levels of angiogenic factors, namely vascular endothelial growth factor (VEGF) and its receptors, endothelin-1 (ET-1) and their downstream molecules, and calculating microvascular density in frontal cortex.Key ���� In the frontal cortex of the endotoxemic model, the expressions of VEGF and KDR with the downstream molecule, eNOS, were diminished sharply in a time-dependent manner, implying significant alterations in the cerebral microcirculation during sepsis. Concomitantly, ET-1, which behaves as a pro-angiogenic factor under the mediation of the ET-B receptor subtype, was similarly downregulated time-dependently. Cerebral capillary density was significantly decreased at 10 hours after LPS administration (56%, p<0.05) compared to that of control brain.������ A recent study reported a significant decrease in cerebral capillary density in a sheep model of sepsis, which is strongly associated with the progression of cerebral pathologies. The current findings are consistent with the findings with this earlier study and provide the first likely mechanisms underlying the altered microcirculation based brain dysfunction in sepsis.