Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE-/- mice.
AngII (angiotensin II) induces atherosclerosis and AAAs (abdominal aortic aneurysms) through multiple proposed mechanisms, including chemotaxis. Therefore, we determined the effects of whole-body deficiency of the chemokine receptor CCR2 (CC chemokine receptor 2) on these diseases. To meet this objective, apoE (apolipoprotein E)-/- mice that were either CCR2+/+ or CCR2-/-, were infused with either saline or AngII (1000 ng.kg-1 of body weight.min-1) for 28 days via mini-osmotic pumps. Deficiency of CCR2 markedly attenuated both atherosclerosis and AAAs, unrelated to systolic blood pressure or plasma cholesterol concentrations. During the course of the present study, we also observed that AngII infusion led to large dilatations that were restricted to the ascending aortic region of apoE-/- mice. The aortic media in most of the dilated area was thickened. In regions of medial thickening, distinct elastin layers were discernable. There was an expansion of the distance between elastin layers in a gradient from the intimal to the adventitial aspect of the media. This pathology differed in a circumscribed area of the anterior region of ascending aortas in which elastin breaks were focal and almost transmural. All regions of the ascending aorta of AngII-infused mice had diffuse medial macrophage accumulation. Deficiency of CCR2 greatly attenuated the AngII-induced lumen dilatation in the ascending aorta. This new model of ascending aortic aneurysms has pathology that differs markedly from AngII-induced atherosclerosis or AAAs, but all vascular pathologies were attenuated by CCR2 deficiency.
Daugherty
Alan
A
Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, U.S.A. Alan.Daugherty@uky.edu
Rateri
Debra L
DL
Charo
Israel F
IF
Owens
A Phillip
AP
Howatt
Deborah A
DA
Cassis
Lisa A
LA
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D008055:Lipids; D054390:Receptors, CCR2; D000804:Angiotensin II; D002784:Cholesterol