title: Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury.
abstract: BACKGROUND
  The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury.
  
  
  RESULTS
  Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg(-/-) mice after lipopolysaccharide challenge. Pik3cg(-/-) mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg(-/-) mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease.
  
  
  CONCLUSIONS
  We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Huang
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Dai
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Cho
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Albertine
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.).
authors.forename: Dean E
authors.initials: DE
authors.lastname: Schraufnagel
authors.affiliation: From Department of Pharmacology (X.H., Z.D., L.C., K.S., J.C., A.B.M., Y.-Y.Z.), Center for Lung and Vascular Biology (X.H., Z.D., L.C., K.S., A.B.M., Y.-Y.Z.), Department of Medicine (D.E.S.), University of Illinois College of Medicine, Chicago; and Departments of Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City (K.H.A.). yyzhao@uic.edu.
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019559:Capillary Leak Syndrome / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000293:injuries / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism / Q000503:physiopathology; D009504:Neutrophils / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology; D011654:Pulmonary Edema / Q000473:pathology / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000473:pathology; D018805:Sepsis / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection; D000077191:Wortmannin
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D000730:Androstadienes; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D005663:Furans; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011725:Pyridines; D011743:Pyrimidines; D011810:Quinoxalines; D011993:Recombinant Fusion Proteins; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D000077191:Wortmannin
keywords: endothelial regeneration; endothelium, vascular; inflammation; vascular diseases; vascular repair
references.citation: Curr Opin Cell Biol. 1999 Apr;11(2):219-25
references.pmid: 10209156
references.citation: Nat Cell Biol. 2005 Feb;7(2):126-36
references.pmid: 15654331
references.citation: Nat Cell Biol. 2005 Feb;7(2):108-10
references.pmid: 15689977
references.citation: J Nat Prod. 2005 Apr;68(4):574-6
references.pmid: 15844952
references.citation: Oncogene. 2005 Apr 21;24(18):2992-3001
references.pmid: 15735710
references.citation: Nat Med. 2005 Sep;11(9):936-43
references.pmid: 16127437
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1094-103
references.pmid: 16183669
references.citation: Physiol Rev. 2006 Jan;86(1):279-367
references.pmid: 16371600
references.citation: J Clin Invest. 2006 Sep;116(9):2316-9
references.pmid: 16955131
references.citation: J Clin Invest. 2006 Sep;116(9):2333-43
references.pmid: 16955137
references.citation: Nat Rev Drug Discov. 2006 Nov;5(11):903-18
references.pmid: 17080027
references.citation: Nat Cell Biol. 2007 Jan;9(1):86-91
references.pmid: 17173040
references.citation: J Immunol. 2007 May 1;178(9):5940-8
references.pmid: 17442978
references.citation: Am J Respir Crit Care Med. 2007 May 1;175(9):958-66
references.pmid: 17322108
references.citation: Blood. 2007 Dec 15;110(13):4243-52
references.pmid: 17827393
references.citation: Pharmacol Rep. 2008 Jan-Feb;60(1):139-43
references.pmid: 18276995
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8292-7
references.pmid: 18544649
references.citation: Trends Biochem Sci. 2009 Mar;34(3):115-27
references.pmid: 19299143
references.citation: Sci Transl Med. 2010 Mar 17;2(23):23ra19
references.pmid: 20375003
references.citation: Cardiovasc Res. 2010 May 1;86(2):202-10
references.pmid: 20068003
references.citation: Nat Rev Mol Cell Biol. 2010 May;11(5):329-41
references.pmid: 20379207
references.citation: Carcinogenesis. 2010 Jun;31(6):1132-41
references.pmid: 20351091
references.citation: J Exp Med. 2010 Aug 2;207(8):1675-85
references.pmid: 20660612
references.citation: N Engl J Med. 2010 Aug 12;363(7):689-91
references.pmid: 20818861
references.citation: Am J Respir Crit Care Med. 2010 Sep 15;182(6):762-73
references.pmid: 20508212
references.citation: Mol Pharmacol. 2010 Nov;78(5):961-70
references.pmid: 20736318
references.citation: Sci Transl Med. 2011 Jun 22;3(88):88ps25
references.pmid: 21697528
references.citation: J Clin Immunol. 2012 Apr;32(2):340-51
references.pmid: 22198681
references.citation: PLoS One. 2012;7(11):e50094
references.pmid: 23185540
references.citation: PLoS One. 2013;8(1):e53808
references.pmid: 23320105
references.citation: Science. 2000 Feb 11;287(5455):1040-6
references.pmid: 10669416
references.citation: Science. 2000 Feb 11;287(5455):1049-53
references.pmid: 10669418
references.citation: Genes Dev. 2000 Jan 15;14(2):142-6
references.pmid: 10702024
references.citation: N Engl J Med. 2000 May 4;342(18):1334-49
references.pmid: 10793167
references.citation: J Immunol. 2001 Dec 1;167(11):6601-8
references.pmid: 11714830
references.citation: Circulation. 2002 Mar 5;105(9):1135-43
references.pmid: 11877368
references.citation: Am J Pathol. 2002 Nov;161(5):1783-96
references.pmid: 12414525
references.citation: J Biol Chem. 2003 Sep 26;278(39):37888-94
references.pmid: 12867420
references.citation: J Immunol. 2004 Jan 1;172(1):449-56
references.pmid: 14688354
references.citation: Nat Rev Mol Cell Biol. 2004 Apr;5(4):261-70
references.pmid: 15071551
references.citation: Physiol Rev. 2004 Jul;84(3):767-801
references.pmid: 15269336
references.citation: Nature. 1985 May 16-22;315(6016):239-42
references.pmid: 2987699
references.citation: J Am Coll Cardiol. 1985 Aug;6(2):369-75
references.pmid: 3160756
references.citation: J Am Coll Cardiol. 1992 Nov 1;20(5):1284-93
references.pmid: 1401633
references.citation: Circulation. 1993 Nov;88(5 Pt 1):2076-85
references.pmid: 8222101
references.citation: Mol Cell Biol. 1997 Mar;17(3):1626-41
references.pmid: 9032290
references.citation: Cell. 1997 Apr 4;89(1):105-14
references.pmid: 9094719
references.citation: Circ Res. 1997 Oct;81(4):618-26
references.pmid: 9314844
references.citation: Blood. 1998 May 15;91(10):3527-61
references.pmid: 9572988
references.citation: N Engl J Med. 1999 Jan 14;340(2):115-26
references.pmid: 9887164