Arterial pathology in canine mucopolysaccharidosis-I and response to therapy

Jeremiah A. Lyons, Patricia I. Dickson, Jonathan Wall, Merry B. Passage, N. Matthew Ellinwood, Emil D. Kakkis, Michael F. McEntee

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Mucopolysaccharidosis-I (MPS-I) is an inherited deficiency of α-L-iduronidase (IdU) that causes lysosomal accumulation of glycosaminoglycans (GAG) in a variety of parenchymal cell types and connective tissues. The fundamental link between genetic mutation and tissue GAG accumulation is clear, but relatively little attention has been given to the morphology or pathogenesis of associated lesions, particularly those affecting the vascular system. The terminal parietal branches of the abdominal aorta were examined from a colony of dogs homozygous (MPS-I affected) or heterozygous (unaffected carrier) for an IdU mutation that eliminated all enzyme activity, and in affected animals treated with human recombinant IdU. High-resolution computed tomography showed that vascular wall thickenings occurred in affected animals near branch points, and associated with low endothelial shear stress. Histologically these asymmetric plaques entailed extensive intimal thickening with disruption of the internal elastic lamina, occluding more than 50% of the vascular lumen in some cases. Immunohistochemistry was used to show that areas of sclerosis contained foamy (GAG laden) macrophages, fibroblasts and smooth muscle cells, with loss of overlying endothelial basement membrane and claudin-5 expression. Lesions contained scattered cells expressing nuclear factor-Β (p65), increased fibronectin and transforming growth factor Β-1 signaling (with nuclear Smad3 accumulation) in comparison to unaffected vessels. Intimal lesion development and morphology was improved by intravenous recombinant enzyme treatment, particularly with immune tolerance to this exogenous protein. The progressive sclerotic vasculopathy of MPS-I shares some morphological and molecular similarities to atherosclerosis, including formation in areas of low shear stress near branch points, and can be reduced or inhibited by intravenous administration of recombinant IdU.

Original languageEnglish (US)
Pages (from-to)665-674
Number of pages10
JournalLaboratory Investigation
Volume91
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

Fingerprint

Iduronidase
Mucopolysaccharidosis I
Canidae
Glycosaminoglycans
Tunica Intima
Pathology
Blood Vessels
Claudin-5
Immune Tolerance
Mutation
Abdominal Aorta
Transforming Growth Factors
Sclerosis
Enzymes
Therapeutics
Fibronectins
Basement Membrane
Intravenous Administration
Smooth Muscle Myocytes
Atherosclerosis

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Lyons, J. A., Dickson, P. I., Wall, J., Passage, M. B., Ellinwood, N. M., Kakkis, E. D., & McEntee, M. F. (2011). Arterial pathology in canine mucopolysaccharidosis-I and response to therapy. Laboratory Investigation, 91(5), 665-674. https://doi.org/10.1038/labinvest.2011.7

Arterial pathology in canine mucopolysaccharidosis-I and response to therapy. / Lyons, Jeremiah A.; Dickson, Patricia I.; Wall, Jonathan; Passage, Merry B.; Ellinwood, N. Matthew; Kakkis, Emil D.; McEntee, Michael F.

In: Laboratory Investigation, Vol. 91, No. 5, 01.05.2011, p. 665-674.

Research output: Contribution to journalArticle

Lyons, JA, Dickson, PI, Wall, J, Passage, MB, Ellinwood, NM, Kakkis, ED & McEntee, MF 2011, 'Arterial pathology in canine mucopolysaccharidosis-I and response to therapy', Laboratory Investigation, vol. 91, no. 5, pp. 665-674. https://doi.org/10.1038/labinvest.2011.7
Lyons, Jeremiah A. ; Dickson, Patricia I. ; Wall, Jonathan ; Passage, Merry B. ; Ellinwood, N. Matthew ; Kakkis, Emil D. ; McEntee, Michael F. / Arterial pathology in canine mucopolysaccharidosis-I and response to therapy. In: Laboratory Investigation. 2011 ; Vol. 91, No. 5. pp. 665-674.
@article{9b362c01f2594889a086651226aecf9c,
title = "Arterial pathology in canine mucopolysaccharidosis-I and response to therapy",
abstract = "Mucopolysaccharidosis-I (MPS-I) is an inherited deficiency of α-L-iduronidase (IdU) that causes lysosomal accumulation of glycosaminoglycans (GAG) in a variety of parenchymal cell types and connective tissues. The fundamental link between genetic mutation and tissue GAG accumulation is clear, but relatively little attention has been given to the morphology or pathogenesis of associated lesions, particularly those affecting the vascular system. The terminal parietal branches of the abdominal aorta were examined from a colony of dogs homozygous (MPS-I affected) or heterozygous (unaffected carrier) for an IdU mutation that eliminated all enzyme activity, and in affected animals treated with human recombinant IdU. High-resolution computed tomography showed that vascular wall thickenings occurred in affected animals near branch points, and associated with low endothelial shear stress. Histologically these asymmetric plaques entailed extensive intimal thickening with disruption of the internal elastic lamina, occluding more than 50{\%} of the vascular lumen in some cases. Immunohistochemistry was used to show that areas of sclerosis contained foamy (GAG laden) macrophages, fibroblasts and smooth muscle cells, with loss of overlying endothelial basement membrane and claudin-5 expression. Lesions contained scattered cells expressing nuclear factor-Β (p65), increased fibronectin and transforming growth factor Β-1 signaling (with nuclear Smad3 accumulation) in comparison to unaffected vessels. Intimal lesion development and morphology was improved by intravenous recombinant enzyme treatment, particularly with immune tolerance to this exogenous protein. The progressive sclerotic vasculopathy of MPS-I shares some morphological and molecular similarities to atherosclerosis, including formation in areas of low shear stress near branch points, and can be reduced or inhibited by intravenous administration of recombinant IdU.",
author = "Lyons, {Jeremiah A.} and Dickson, {Patricia I.} and Jonathan Wall and Passage, {Merry B.} and Ellinwood, {N. Matthew} and Kakkis, {Emil D.} and McEntee, {Michael F.}",
year = "2011",
month = "5",
day = "1",
doi = "10.1038/labinvest.2011.7",
language = "English (US)",
volume = "91",
pages = "665--674",
journal = "Laboratory Investigation",
issn = "0023-6837",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Arterial pathology in canine mucopolysaccharidosis-I and response to therapy

AU - Lyons, Jeremiah A.

AU - Dickson, Patricia I.

AU - Wall, Jonathan

AU - Passage, Merry B.

AU - Ellinwood, N. Matthew

AU - Kakkis, Emil D.

AU - McEntee, Michael F.

PY - 2011/5/1

Y1 - 2011/5/1

N2 - Mucopolysaccharidosis-I (MPS-I) is an inherited deficiency of α-L-iduronidase (IdU) that causes lysosomal accumulation of glycosaminoglycans (GAG) in a variety of parenchymal cell types and connective tissues. The fundamental link between genetic mutation and tissue GAG accumulation is clear, but relatively little attention has been given to the morphology or pathogenesis of associated lesions, particularly those affecting the vascular system. The terminal parietal branches of the abdominal aorta were examined from a colony of dogs homozygous (MPS-I affected) or heterozygous (unaffected carrier) for an IdU mutation that eliminated all enzyme activity, and in affected animals treated with human recombinant IdU. High-resolution computed tomography showed that vascular wall thickenings occurred in affected animals near branch points, and associated with low endothelial shear stress. Histologically these asymmetric plaques entailed extensive intimal thickening with disruption of the internal elastic lamina, occluding more than 50% of the vascular lumen in some cases. Immunohistochemistry was used to show that areas of sclerosis contained foamy (GAG laden) macrophages, fibroblasts and smooth muscle cells, with loss of overlying endothelial basement membrane and claudin-5 expression. Lesions contained scattered cells expressing nuclear factor-Β (p65), increased fibronectin and transforming growth factor Β-1 signaling (with nuclear Smad3 accumulation) in comparison to unaffected vessels. Intimal lesion development and morphology was improved by intravenous recombinant enzyme treatment, particularly with immune tolerance to this exogenous protein. The progressive sclerotic vasculopathy of MPS-I shares some morphological and molecular similarities to atherosclerosis, including formation in areas of low shear stress near branch points, and can be reduced or inhibited by intravenous administration of recombinant IdU.

AB - Mucopolysaccharidosis-I (MPS-I) is an inherited deficiency of α-L-iduronidase (IdU) that causes lysosomal accumulation of glycosaminoglycans (GAG) in a variety of parenchymal cell types and connective tissues. The fundamental link between genetic mutation and tissue GAG accumulation is clear, but relatively little attention has been given to the morphology or pathogenesis of associated lesions, particularly those affecting the vascular system. The terminal parietal branches of the abdominal aorta were examined from a colony of dogs homozygous (MPS-I affected) or heterozygous (unaffected carrier) for an IdU mutation that eliminated all enzyme activity, and in affected animals treated with human recombinant IdU. High-resolution computed tomography showed that vascular wall thickenings occurred in affected animals near branch points, and associated with low endothelial shear stress. Histologically these asymmetric plaques entailed extensive intimal thickening with disruption of the internal elastic lamina, occluding more than 50% of the vascular lumen in some cases. Immunohistochemistry was used to show that areas of sclerosis contained foamy (GAG laden) macrophages, fibroblasts and smooth muscle cells, with loss of overlying endothelial basement membrane and claudin-5 expression. Lesions contained scattered cells expressing nuclear factor-Β (p65), increased fibronectin and transforming growth factor Β-1 signaling (with nuclear Smad3 accumulation) in comparison to unaffected vessels. Intimal lesion development and morphology was improved by intravenous recombinant enzyme treatment, particularly with immune tolerance to this exogenous protein. The progressive sclerotic vasculopathy of MPS-I shares some morphological and molecular similarities to atherosclerosis, including formation in areas of low shear stress near branch points, and can be reduced or inhibited by intravenous administration of recombinant IdU.

UR - http://www.scopus.com/inward/record.url?scp=79955546366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955546366&partnerID=8YFLogxK

U2 - 10.1038/labinvest.2011.7

DO - 10.1038/labinvest.2011.7

M3 - Article

VL - 91

SP - 665

EP - 674

JO - Laboratory Investigation

JF - Laboratory Investigation

SN - 0023-6837

IS - 5

ER -