Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver

Adam C. Straub, Donna B. Stolz, Mark A. Ross, Araceli Hernández-Zavala, Nicole V. Soucy, Linda R. Klei, Aaron Barchowsky

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Abstract

Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. Conclusion: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver. Copyright © 2006 by the American Association for the Study of Liver Diseases.
Original languageAmerican English
Pages (from-to)205-212
Number of pages8
JournalHepatology
DOIs
StatePublished - 1 Jan 2007
Externally publishedYes

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Arsenic
Endothelial Cells
Liver
Endothelium
Blood Vessels
CD31 Antigens
Animal Structures
Adherens Junctions
Caveolin 1
Caveolae
GTP Phosphohydrolases
Arterioles
Portal Hypertension
Basement Membrane
Constriction
Drinking Water
Fluorescent Antibody Technique
Hepatocytes
Fibrosis
Membranes

Cite this

Straub, Adam C. ; Stolz, Donna B. ; Ross, Mark A. ; Hernández-Zavala, Araceli ; Soucy, Nicole V. ; Klei, Linda R. ; Barchowsky, Aaron. / Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver. In: Hepatology. 2007 ; pp. 205-212.
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abstract = "Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. Conclusion: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver. Copyright {\circledC} 2006 by the American Association for the Study of Liver Diseases.",
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Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver. / Straub, Adam C.; Stolz, Donna B.; Ross, Mark A.; Hernández-Zavala, Araceli; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron.

In: Hepatology, 01.01.2007, p. 205-212.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver

AU - Straub, Adam C.

AU - Stolz, Donna B.

AU - Ross, Mark A.

AU - Hernández-Zavala, Araceli

AU - Soucy, Nicole V.

AU - Klei, Linda R.

AU - Barchowsky, Aaron

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. Conclusion: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver. Copyright © 2006 by the American Association for the Study of Liver Diseases.

AB - Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. Conclusion: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver. Copyright © 2006 by the American Association for the Study of Liver Diseases.

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DO - 10.1002/hep.21444

M3 - Article

SP - 205

EP - 212

JO - Hepatology

JF - Hepatology

SN - 0270-9139

ER -