Dextran sulfate sodium leads to chronic colitis and pathological angiogenesis in Endoglin heterozygous mice.
BACKGROUND
Pathological angiogenesis is an intrinsic component of chronic intestinal inflammation, which results in remodeling and expansion of the gut microvascular bed. Endoglin is essential for endothelial cell function and physiological angiogenesis. In this study we investigated its potential role in the regulation of inflammation by testing the response of Endoglin heterozygous (Eng(+/-)) mice to experimental colitis.


METHODS
C57BL/6 Eng(+/-) and littermate control mice drank water supplemented with 3% dextran sulfate sodium (DSS) for 5 days and were monitored for up to 26 days for clinical signs of colitis. Inflammation, crypt damage, and angiogenic index were scored on histological sections of distal colon. Levels of the vascular endothelial growth factor (VEGF) and angiopoietins were measured by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and/or Western blots. Vascular permeability was assessed using Evans Blue.


RESULTS
Eng(+/-) and control mice developed acute colitis, which peaked at day 9. While control mice recovered by days 19-26, Eng(+/-) mice progressed to chronic colitis and showed numerous vascular protrusions penetrating into the serosa of the inflamed distal colon. Prior to DSS induction, VEGF levels and vascular permeability were higher in the distal colon of Eng(+/-) mice, while angiopoietin 1 and 2 levels were unchanged. In the chronic phase of colitis, VEGF levels were increased in both groups of mice and remained significantly higher in the Eng(+/-) mice.


CONCLUSIONS
Higher VEGF levels and increased vascular permeability in the distal colon may predispose Eng(+/-) mice to progress to chronic and persistent bowel inflammation, associated with pathological angiogenesis.
Jerkic
Mirjana
M
Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario, Canada.
Peter
Madonna
M
Ardelean
Daniela
D
Fine
Michael
M
Konerding
Moritz A
MA
Letarte
Michelle
M
D000208:Acute Disease; D042682:Angiopoietins / Q000032:analysis; D000818:Animals; D002199:Capillary Permeability; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D000071063:Endoglin; D006579:Heterozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics*; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000378:metabolism
D042682:Angiopoietins; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D042442:Vascular Endothelial Growth Factors; D016264:Dextran Sulfate