HIF-1α Enhances Vascular Endothelial Cell Permeability Through Degradation and Translocation of Vascular Endothelial Cadherin and Claudin-5 in Rats With Burn Injury

Abstract

Background The mechanism underlying burn injury-induced enhanced vascular endothelial permeability and consequent body fluid extravasation is unclear. Here, the rat aortic endothelial cells (RAECs) were treated with the serum derived from rats with burn injury to elucidate the mechanism Methods Sprague-Dawley (SD) rats were grouped as follows (10 rats/group): control, 2, 4, 8, 12, and 24 h post-burn groups. The heart, liver, kidney, lung, jejunum, and ileum of rats injected with 2% Evans blue (EB) through the tail vein were excised to detect the EB level in each organ. The serum levels of hypoxia-inducible factor-1α (HIF-1α) and endothelin-1 (ET-1) were examined using enzyme-linked immunosorbent assay (ELISA). The effect of serum from 12 h post-burn group on the membrane permeability of RAEC monolayer, as well as on the mRNA and protein levels of ET-1, endothelin receptor A (ETA), ETB, and zonula occludens (ZO-1), were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The membrane permeability of GV230/HIF-1α-transfected or shRNA-HIF-1α-transfected RAECs, as well as the expression levels of HIF-1α, ET-1, ETA, ETB, vascular endothelial (VE)-cadherin, and claudin-5, were analyzed using qRT-PCR and western blotting, while the localization of VE-cadherin and claudin-5 was examined using immunofluorescence Results The serum HIF-1α and ET-1 levels in the burn groups, which peaked at 12 h post-burn, were significantly upregulated (P<0.01) when compared with those in the control group. Additionally, the serum HIF-1α levels were positively correlated with vascular permeability. Compared with the shRNA-negative control-transfected RAECs, the shRNA-II/HIF-1α-transfected RAECs exhibited downregulated expression of HIF-1α, ET-1, ETA, and ETB (P<0.01), and upregulated expression of ZO-1, claudin-5, and VE-cadherin (P<0.05). Compared with the GV230-transfected RAECs, the GV230/HIF-1α-transfected RAECs exhibited upregulated expression of HIF-1α, ET-1, ETA, and ETB (P<0.01), and downregulated expression of ZO-1, claudin-5, and VE-cadherin (P<0.05). The GV230/HIF-1α-transfected RAECs exhibited degradation and translocation of VE-cadherin and claudin-5 Conclusion In addition to degradation of VE-cadherin and claudin-5, HIF-1α mediated enhanced endothelial cell permeability through upregulation of ET-1, ETA, and ETB, and downregulation of ZO-1 and VE-cadherin in rats with burn injury

Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair

“…These results indicate that HIF-1α is induced during inflammatory EC injury and that inflammatory LEC injury occurs via HIF-1α [ 44 ]. In a rat model of burn injury, serum levels of HIF-1α increase to a peak at 12 h post-burn and are associated with increases in lung vascular permeability [ 45 ]. In isolated rat aortic LECs, increased HIF-1α expression leads to reductions in the expression of VE-cadherin [ 45 ], a key adhesion molecule located at the EC–EC junctions.…”

“…In a rat model of burn injury, serum levels of HIF-1α increase to a peak at 12 h post-burn and are associated with increases in lung vascular permeability [ 45 ]. In isolated rat aortic LECs, increased HIF-1α expression leads to reductions in the expression of VE-cadherin [ 45 ], a key adhesion molecule located at the EC–EC junctions. Conversely, decreased HIF-1α expression results in increased VE-cadherin expression [ 45 ].…”

“…In isolated rat aortic LECs, increased HIF-1α expression leads to reductions in the expression of VE-cadherin [ 45 ], a key adhesion molecule located at the EC–EC junctions. Conversely, decreased HIF-1α expression results in increased VE-cadherin expression [ 45 ]. In another study of rat LECs, HIF-1α siRNA treatment reduced LEC permeability following hypertonicity and hypoxia [ 46 ].…”

“…FG-4497 is an example of a PHD2 inhibitor that activates HIF-2 signaling, and in turn reduces LEC injury in a mouse model of endotoxemia sepsis [ 78 ]. However, the delivery of HIF agonists or antagonists will need to be appropriately timed, given that HIF-1 has been shown to increase LEC injury [ 45 , 46 ] but accelerate repair [ 66 , 67 ], while HIF-2 has been shown to reduce lung injury [ 48 , 49 , 51 ] but impair repair [ 72 ] ( Figure 3 ). Future studies could attempt to develop novel diagnostic tests that identify the phase of injury or repair, thus informing whether injury or repair pathways should be targeted.…”

Researches on cognitive sequelae of burn injury: Current status and advances

“…The increased permeability of BBB after severe burns in the rat model may also be related to the decreased expression of zonula occludens1 (ZO-1) in tight junctions (Liu et al, 2011). In rats with burn injury, the expression of hypoxia inducible factor-1 (HIF-1α) was upregulated, which consequently enhanced endothelial cell permeability through downregulation of Claudin5, ZO-1, VE-cadherin (Jiang et al, 2021). Umbilical cord-derived mesenchymal stem cells can protect the integrity of BBB after burns by decreasing the IL-6 and IL-1β level, protecting the tight junction, as well as reducing transcytosis and neuroinflammation (Yang et al, 2020).…”