Inadequate reinforcement of transmedial disruptions at branch points subtends aortic aneurysm formation in apolipoprotein-E-deficient mice.
BACKGROUND
Infusion of angiotensin-II (Ang-II) in apolipoprotein-E-deficient mice (Apo-E(-/-)) results in suprarenal abdominal aortic aneurysm (AAA) in 30-85% of cases. This study identifies the apparent mechanism by which some animals do, but others do not, develop AAA in this model.


METHODS
Male Apo-E(-/-) mice were infused with Ang-II (n=21) or saline (n=6) and sacrificed at 4 weeks. Aortas were excised, embedded in paraffin, sectioned (250 μm intervals), and stained. Sites of transmedial disruption (TMD) were identified and characterized, and their relationship to the 4 major aortic side branches (celiac, superior mesenteric, and renals) were determined.


RESULTS
The frequency of TMDs in Ang-II-infused mice that formed AAA (n=9) was similar to those that did not (n=12) (AAA vs. no-AAA: 25 of 36[69%] vs. 28 of 48[58%] branches, P=.3 by chi-square). All TMDs were at branch points. However, in animals with AAA, the mean maximum length of the TMDs was significantly larger (1.94±1.6 vs. 0.65±0.5mm, P=.007 by Mann Whitney U test), the #mac-2(+) macrophages per 0.01mm(2) of defect area was greater (32±10 vs. 19±11, P<.02 by Kruskal-Wallis with Conover-Inman post hoc), the % area of attempted repair occupied by collagen was less (17±13% vs. 44±15%, P=.0009 by Mann Whitney U test), and the density of collagen per unit length of media missing was also markedly less (0.13±0.2 vs. 1.14±1.0, P=.0001 by Mann Whitney U test).


CONCLUSIONS
Reinforcement of transmedial defects at branch points by wall matrix is a key intrinsic player in limiting AAA formation in the Ang-II-infused, Apo E(-/-) mouse and a potentially important mechanism-based therapeutic target for management of small, slowly progressing aneurysms.
Institute for Medical Research-IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Lilach
L
Gavish
Department of Cardiology, The Hebrew University-Hadassah Medical School and University Hospital, Jerusalem, Israel.
Ronen
R
Beeri
Department of Cardiology, The Hebrew University-Hadassah Medical School and University Hospital, Jerusalem, Israel.
Dan
D
Gilon
Department of Vascular Surgery, The Hebrew University-Hadassah Medical School and University Hospital, Jerusalem, Israel.
Chen
C
Rubinstein
Department of Vascular Surgery, The Hebrew University-Hadassah Medical School and University Hospital, Jerusalem, Israel.
Yacov
Y
Berlatzky
Institute for Medical Research-IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Leah Y
LY
Gavish
Department of Cardiology, The Hebrew University-Hadassah Medical School and University Hospital, Jerusalem, Israel.
Atilla
A
Bulut
Division of Veterinary Surgery, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Mickey
M
Harlev
Department of Surgery, Shaarei Zedek Hospital, Jerusalem, Israel.
Petachia
P
Reissman
Institute for Medical Research-IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: Gertz@cc.huji.ac.il.
S David
SD
Gertz
D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D016009:Chi-Square Distribution; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D008264:Macrophages / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology*
D001057:Apolipoproteins E; D000804:Angiotensin II; D003094:Collagen
Abdominal aortic aneurysm; Aneurysm; Angiotensin-II; Apolipoprotein e-deficient mice