Transiently heightened angiotensin II has distinct effects on atherosclerosis and aneurysm formation in hyperlipidemic mice.
Experimentally sustained increase in angiotensin II (AngII) promotes tissue destruction in various cardiovascular disorders. We examined whether transiently heightened AngII affects subsequent atherosclerosis and aneurysm formation. AngII or saline was administered for 2 weeks to apolipoprotein E (apoE)-deficient mice. Mice were sacrificed at the end of the 2-week infusion or 6- or 14 weeks later. Short-term AngII did not affect atherosclerosis immediately following the infusion or 6 weeks later. By contrast, 14 weeks after infusion there was remarkably more atherosclerosis in previously AngII-exposed mice. Preceding the build up of atherosclerotic lesions, AngII-exposure increased mRNA expression and immunostaining of monocyte chemoattractant protein-1 (MCP-1) and its receptor, CCR2. This was followed by greater macrophage-positivity in AngII-exposed aortae. In contrast to the delayed effects on atherosclerosis, 20% of mice were found to have abdominal aneurysms at the end of AngII-exposure. This effect was not contingent on blood pressure. Moreover, despite amplification in atherosclerosis following AngII, no aneurysms were found 14 weeks later. Our studies reveal that even transient exposure to AngII primes the vessel for subsequent amplification of atherosclerosis which involves activation of MCP-1/CCR2 and influx of macrophages into the nascent atherosclerotic plaque. By contrast, transient AngII-exposure causes prompt aneurysm formation that does not parallel atherosclerosis and disappears even in the face of progressively greater atherosclerotic lesions.
Ayabe
Nobuhiko
N
Department of Pediatrics, MCN C4204, Vanderbilt University Medical Center, Nashville, TN 37232-2584, USA.
Babaev
Vladimir R
VR
Tang
Yiwei
Y
Tanizawa
Takakuni
T
Fogo
Agnes B
AB
Linton
Macrae F
MF
Ichikawa
Iekuni
I
Fazio
Sergio
S
Kon
Valentina
V
D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D006949:Hyperlipidemias / Q000150:complications* / Q000378:metabolism; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D000804:Angiotensin II; D012313:RNA