Genetically engineered resistance for MMP collagenases promotes abdominal aortic aneurysm formation in mice infused with angiotensin II.
Clinical evidence links increased aortic collagen content and stiffness to abdominal aortic aneurysm (AAA) formation. However, the possibility that excess collagen contributes to AAA formation remains untested. We investigated the hypothesis that augmented collagen promotes AAA formation, and employed apoE-null mice expressing collagenase-resistant mutant collagen (Col(R/R)/apoE(-/-)), heterozygote (Col(R/+)/apoE(-/-)), or wild-type collagen (Col(+/+)/apoE(-/-)) infused with angiotensin II to induce AAA. As expected, the aortas of Col(R/R)/apoE(-/-) mice contained more interstitial collagen than those from the other groups. Angiotensin II treatment elicited more AAA formation in Col(R/R)/apoE(-/-) mice than Col(R/+)/apoE(-/-) or Col(+/+)/apoE(-/-) mice. Aortic circumferences correlated positively with collagen content, determined by picrosirius red and Masson trichrome staining. Mechanical testing of aortas of Col(R/R)/apoE(-/-) mice showed increased stiffness and susceptibility to mechanical failure compared to those of Col(+/+)/apoE(-/-) mice. Optical analysis further indicated altered collagen fiber orientation in the adventitia of Col(R/R)/apoE(-/-) mice. These results demonstrate that collagen content regulates aortic biomechanical properties and influences AAA formation.
Deguchi
Jun-o
JO
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Huang
Hayden
H
Libby
Peter
P
Aikawa
Elena
E
Whittaker
Peter
P
Sylvan
Jeremy
J
Lee
Richard T
RT
Aikawa
Masanori
M
D000704:Analysis of Variance; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000378:metabolism; D001696:Biomechanical Phenomena; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D003238:Connective Tissue / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D006651:Histocytochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D001057:Apolipoproteins E; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D017364:Collagenases