Endothelial cell-specific deficiency of Ang II type 1a receptors attenuates Ang II-induced ascending aortic aneurysms in LDL receptor-/- mice.
BACKGROUND
Human studies and mouse models have provided evidence for angiotensin II (Ang II)-based mechanisms as an underlying cause of aneurysms localized to the ascending aorta. In agreement with this associative evidence, we have published recently that Ang II infusion induces aneurysmal pathology in the ascending aorta.


OBJECTIVE
The aim of this study was to define the role of angiotensin II type 1a (AT(1a)) receptors and their cellular location in Ang II-induced ascending aortic aneurysms (AAs).


RESULTS
Male LDL receptor(-/-) mice were fed a saturated fat-enriched diet for 1 week before osmotic mini-pump implantation and infused with either saline or Ang II (1000 ng/kg per minute) for 28 days. Intimal surface areas of ascending aortas were measured to quantify ascending AAs. Whole body AT(1a) receptor deficiency ablated Ang II-induced ascending AAs (P<0.001). To determine the role of AT(1a) receptors on leukocytes, LDL receptor(-/-)×AT(1a) receptor(+/+) or AT(1a) receptor(-/-) mice were irradiated and repopulated with bone marrow-derived cells isolated from either AT(1a) receptor(+/+) or AT(1a) receptor(-/-) mice. Deficiency of AT(1a) receptors in bone marrow-derived cells had no effect on Ang II-induced ascending AAs. To determine the role of AT(1a) receptors on vascular wall cells, we developed AT(1a) receptor floxed mice with depletion on either smooth muscle or endothelial cells using Cre driven by either SM22 or Tek, respectively. AT(1a) receptor deletion in smooth muscle cells had no effect on ascending AAs. In contrast, endothelial-specific depletion attenuated this pathology.


CONCLUSIONS
Ang II infusion promotes aneurysms in the ascending aorta via stimulation of AT(1a) receptors that are expressed on endothelial cells.
Saha Cardiovascular Research Center, BBSRB, Room 243, University of Kentucky, Lexington, KY 40536-0509, USA.
Debra L
DL
Rateri
Jessica J
JJ
Moorleghen
Anju
A
Balakrishnan
A Phillip
AP
Owens
Deborah A
DA
Howatt
Venkateswaran
V
Subramanian
Aruna
A
Poduri
Richard
R
Charnigo
Lisa A
LA
Cassis
Alan
A
Daugherty
D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001014:Aortic Aneurysm / Q000209:etiology* / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D044140:Receptor, Angiotensin, Type 1; D011973:Receptors, LDL; D000804:Angiotensin II
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