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Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension

Hilscher, Moira B. ; Sehrawat, Tejasav ; Arab, Juan P. ; Zeng, Zhutian ; Gao, Jinhang ; Liu, Mengfei ; Kostallari, Enis ; Gao, Yandong ; Simonetto, Douglas A. ; Yaqoob, Usman ; Cao, Sheng ; Revzin, Alexander ; Beyder, Arthur ; Wang, Rong A. ; Kamath, Patrick S. ; Kubes, Paul ; Shah, Vijay H.

Gastroenterology (New York, N.Y. 1943), 2019-07, Vol.157 (1), p.193-209.e9 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension
Autor: Hilscher, Moira B. ; Sehrawat, Tejasav ; Arab, Juan P. ; Zeng, Zhutian ; Gao, Jinhang ; Liu, Mengfei ; Kostallari, Enis ; Gao, Yandong ; Simonetto, Douglas A. ; Yaqoob, Usman ; Cao, Sheng ; Revzin, Alexander ; Beyder, Arthur ; Wang, Rong A. ; Kamath, Patrick S. ; Kubes, Paul ; Shah, Vijay H.
Assuntos: Animals ; Calcium Signaling ; Capillaries - cytology ; Capillaries - metabolism ; Chemokine ; Chemokine CXCL1 - metabolism ; Congestive Hepatopathy ; Endothelial Cells - metabolism ; Extracellular Matrix ; Extracellular Traps ; Hydrolases - genetics ; Hypertension, Portal - metabolism ; In Vitro Techniques ; Integrins - metabolism ; Leukocyte Elastase - genetics ; Ligation ; Liver - blood supply ; Liver - metabolism ; Mechanotransduction, Cellular ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mouse Model ; Neutrophil Infiltration ; Portal Pressure ; Protein-Arginine Deiminase Type 4 ; Receptor, Notch1 - genetics ; Stress, Mechanical ; Thrombosis - metabolism ; Vena Cava, Inferior - surgery
É parte de: Gastroenterology (New York, N.Y. 1943), 2019-07, Vol.157 (1), p.193-209.e9
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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MBH contributed study concept and design, acquisition of data, analysis and interpretation of data, statistical analysis, and drafting of the manuscript. JPAV and TS contributed acquisition of data and analysis and interpretation of data. ZZ, EK, JG and YG contributed acquisition of data. DAS contributed critical revision of the manuscript for important intellectual content. UY contributed acquisition of data and technical support. SC, AR, AB, PSK, DS, ML, and PK contributed critical revision of the manuscript for important intellectual content. VHS contributed study concept and design, critical revision of the manuscript for important intellectual content, and study supervision.
Author Contributions
Descrição: Mechanical forces contribute to portal hypertension (PHTN) and fibrogenesis. We investigated the mechanisms by which forces are transduced by liver sinusoidal endothelial cells (LSECs) into pressure and matrix changes. We isolated primary LSECs from mice and induced mechanical stretch with a Flexcell device, to recapitulate the pulsatile forces induced by congestion, and performed microarray and RNA-sequencing analyses to identify gene expression patterns associated with stretch. We also performed studies with C57BL/6 mice (controls), mice with deletion of neutrophil elastase (NE–/–) or peptidyl arginine deiminase type IV (Pad4–/–) (enzymes that formation of neutrophil extracellular traps [NETs]), and mice with LSEC-specific deletion of Notch1 (Notch1iΔEC). We performed partial ligation of the suprahepatic inferior vena cava (pIVCL) to simulate congestive hepatopathy-induced portal hypertension in mice; some mice were given subcutaneous injections of sivelestat or underwent bile-duct ligation. Portal pressure was measured using a digital blood pressure analyzer and we performed intravital imaging of livers of mice. Expression of the neutrophil chemoattractant CXCL1 was up-regulated in primary LSECs exposed to mechanical stretch, compared with unexposed cells. Intravital imaging of livers in control mice revealed sinusoidal complexes of neutrophils and platelets and formation of NETs after pIVCL. NE–/– and Pad4–/– mice had lower portal pressure and livers had less fibrin compared with control mice after pIVCL and bile-duct ligation; neutrophil recruitment into sinusoidal lumen of liver might increase portal pressure by promoting sinusoid microthrombi. RNA-sequencing of LSECs identified proteins in mechanosensitive signaling pathways that are altered in response to mechanical stretch, including integrins, Notch1, and calcium signaling pathways. Mechanical stretch of LSECs increased expression of CXCL1 via integrin-dependent activation of transcription factors regulated by Notch and its interaction with the mechanosensitive piezo calcium channel. In studies of LSECs and knockout mice, we identified mechanosensitive angiocrine signals released by LSECs which promote PHTN by recruiting sinusoidal neutrophils and promoting formation of NETs and microthrombi. Strategies to target these pathways might be developed for treatment of PHTN. RNA-sequencing accession number: GSE119547 [Display omitted]
Editor: United States: Elsevier Inc
Idioma: Inglês

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Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension

Hilscher, Moira B. ; Sehrawat, Tejasav ; Arab, Juan P. ; Zeng, Zhutian ; Gao, Jinhang ; Liu, Mengfei ; Kostallari, Enis ; Gao, Yandong ; Simonetto, Douglas A. ; Yaqoob, Usman ; Cao, Sheng ; Revzin, Alexander ; Beyder, Arthur ; Wang, Rong A. ; Kamath, Patrick S. ; Kubes, Paul ; Shah, Vijay H.

United States: Elsevier Inc

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