title: Pigment epithelium-derived factor regulates microvascular permeability through adipose triglyceride lipase in sepsis.
abstract: The integrity of the vascular barrier, which is essential to blood vessel homoeostasis, can be disrupted by a variety of soluble permeability factors during sepsis. Pigment epithelium-derived factor (PEDF), a potent endogenous anti-angiogenic molecule, is significantly increased in sepsis, but its role in endothelial dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF in vivo using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and in vitro using human dermal microvascular endothelial cells (HDMECs). In addition, PEDF was inhibited using a PEDF-monoclonal antibody (PEDF-mAb) or recombinant lentivirus vectors targeting PEDF receptors, including adipose triglyceride lipase (ATGL) and laminin receptor (LR). Our results showed that exogenous PEDF induced vascular hyperpermeability, as measured by extravasation of Evan's Blue (EB), dextran and microspheres in the skin, blood, trachea and cremaster muscle, both in a normal state and under conditions of sepsis. In control and LR-shRNA-treated HDMECs, PEDF alone or in combination with inflammatory mediators resulted in activation of RhoA, which was accompanied by actin rearrangement and disassembly of intercellular junctions, impairing endothelial barrier function. But in ATGL-shRNA-treated HDMECs, PEDF failed to induce the aforementioned alterations, suggesting that PEDF-induced hyperpermeability was mediated through the ATGL receptor. These results reveal a novel role for PEDF as a potential vasoactive substance in septic vascular hyperpermeability. Furthermore, our results suggest that PEDF and ATGL may serve as therapeutic targets for managing vascular hyperpermeability in sepsis.
authors.affiliation: *Institute of Burn Research, Southwest Hospital, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Diseases Proteomics, Chongqing, 400038, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: †Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, PR China.
authors.forename: Jiongyu
authors.initials: J
authors.lastname: Hu
authors.affiliation: ‡Department of Pathology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, PR China.
authors.forename: Guangning
authors.initials: G
authors.lastname: Yan
authors.affiliation: *Institute of Burn Research, Southwest Hospital, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Diseases Proteomics, Chongqing, 400038, PR China.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Li
authors.affiliation: *Institute of Burn Research, Southwest Hospital, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Diseases Proteomics, Chongqing, 400038, PR China.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Zhang
authors.affiliation: *Institute of Burn Research, Southwest Hospital, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Diseases Proteomics, Chongqing, 400038, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: †Department of Endocrinology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, PR China.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.affiliation: *Institute of Burn Research, Southwest Hospital, Third Military Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Diseases Proteomics, Chongqing, 400038, PR China.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000097:blood* / Q000494:pharmacology; D034622:RNA Interference; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000201:enzymology / Q000503:physiopathology*; D015843:Serpins / Q000097:blood* / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor; D000217:Acyltransferases
chemical_list: D005136:Eye Proteins; D008049:Lipase; D009414:Nerve Growth Factors; D018013:Receptors, Neuropeptide; D015843:Serpins; D062826:Zonula Occludens-1 Protein; D020742:rhoA GTP-Binding Protein; D000099174:Pigment Epithelium-Derived Factor; C569043:Tjp1 protein, mouse; C400531:pigment epithelium-derived factor receptor; C494794:PNPLA2 protein, human; D000217:Acyltransferases; C494445:PNPLA2 protein, mouse