scholarly journals mTORC2 Activation Mediated by Mesenchymal Stem Cell-Secreted Hepatocyte Growth Factors for the Recovery of Lipopolysaccharide-Induced Vascular Endothelial Barrier

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Shan-Shan Meng ◽  
Feng-Mei Guo ◽  
Li-Li Huang ◽  
Ying-Zi Huang ◽  
Jian-Feng Xie ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Endothelial Barrier ◽  
Vascular Endothelial ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
Microvascular Endothelial ◽  
Hepatocyte Growth

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by pulmonary microvascular endothelial barrier dysfunction. Mesenchymal stem cell-secreted hepatocyte growth factor (HGF) has positive effects of lipopolysaccharide- (LPS-) induced pulmonary endothelial barrier. Studies have exhibited the mammalian TORC1 (mTORC1) signaling is of potent angiogenesis effects. The mTOR protein kinase has two distinct multiprotein complexes mTORC1 and mTORC2 that regulate different branches of the mTOR network. However, detailed mTORC2 mechanisms of HGF protective effects remain poorly defined. Therefore, the aim of this study was to determine whether mTORC2 mediated protective effects of MSC-secreted HGF against LPS-induced pulmonary microvascular endothelial barrier dysfunction activated like mTORC1 activation. We introduced MSC-PMVEC coculture transwell system and recombinant murine HGF on LPS-induced endothelial cell barrier dysfunction in vitro and then explored potential mechanisms by lentivirus vector-mediated HGF, mTORC1 (raptor), and mTORC2 (rictor) gene knockdown modification. Endothelial paracellular and transcellular permeability, adherent junction protein (VE-Cadherin), cell proliferation, apoptosis, and mTOR-associated proteins were tested. These revealed that HGF could promote quick reestablishment of adherent junction VE-cadherin and decrease endothelial paracellular and transcellular permeability during LSP-induced endothelial dysfunction with the involvement of mTORC2 (rictor) and mTORC1 (raptor) pathways. Raptor and rictor knockdown in LPS-induced PMEVECs with stimulation of HGF increased apoptosis ratio, activated Cleaved-Caspase-3 expression, and downregulated cell proliferation. Moreover, mTORC2/Akt but not mTORC2/PKC had significance on HGF endothelial protective effects. Taken together, these highlight activation mTORC2 pathway could also contribute to vascular endothelial barrier recovery by MSC-secreted HGF in LPS stimulation.

scholarly journals ASK1-p38 cascaded signal mediates pulmonary microvascular endothelial barrier injury induced by the return of PHSML in rats

RSC Advances ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 4870-4875
Author(s):  
Muhammad Fawad ◽  
Muhammad Abbas ◽  
Limin Zhang ◽  
Yuping Zhang ◽  
Yaxiong Guo
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hemorrhagic Shock ◽  
Endothelial Barrier ◽  
Vascular Endothelial ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
Mesenteric Lymph ◽  
Microvascular Endothelial

The return of post-hemorrhagic shock mesenteric lymph (PHSML) induces pulmonary vascular endothelial barrier dysfunction, which results in acute lung injury.

scholarly journals The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1489
Author(s):  
Ruben M. L. Colunga Biancatelli ◽  
Pavel Solopov ◽  
Betsy Gregory ◽  
John D. Catravas
Keyword(s):  
Endothelial Cells ◽  
Hydrochloric Acid ◽  
Human Lung ◽  
Hsp90 Inhibitor ◽  
Endothelial Barrier ◽  
Microvascular Endothelial Cells ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Endothelial Barrier Dysfunction ◽  
Microvascular Endothelial

Exposure to hydrochloric acid (HCl) leads acutely to asthma-like symptoms, acute respiratory distress syndrome (ARDS), including compromised alveolo-capillary barrier, and respiratory failure. To better understand the direct effects of HCl on pulmonary endothelial function, we studied the characteristics of HCl-induced endothelial barrier dysfunction in primary cultures of human lung microvascular endothelial cells (HLMVEC), defined the involved molecular pathways, and tested the potentially beneficial effects of Heat Shock Protein 90 (HSP90) inhibitors. HCl impaired barrier function in a time- and concentration-dependent manner and was associated with activation of Protein Kinase B (AKT), Ras homolog family member A (RhoA) and myosin light chain 2 (MLC2), as well as loss of plasmalemmal VE-cadherin, rearrangement of cortical actin, and appearance of inter-endothelial gaps. Pre-treatment or post-treatment of HLMVEC with AUY-922, a third-generation HSP90 inhibitor, prevented and restored HCl-induced endothelial barrier dysfunction. AUY-922 increased the expression of HSP70 and inhibited the activation (phosphorylation) of extracellular-signal regulated kinase (ERK) and AKT. AUY-922 also prevented the HCl-induced activation of RhoA and MLC2 and the internalization of plasmalemmal VE-cadherin. We conclude that, by increasing the expression of cytoprotective proteins, interfering with actomyosin contractility, and enhancing the expression of junction proteins, inhibition of HSP90 may represent a useful approach for the management of HCl-induced endothelial dysfunction and acute lung injury.

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