RATIONALE: 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). METHODS AND 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.
RATIONALE: 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). METHODS AND 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.
Authors: Gary G Deng; Baby Martin-McNulty; Drew A Sukovich; Ana Freay; Meredith Halks-Miller; Therese Thinnes; David J Loskutoff; Peter Carmeliet; William P Dole; Yi-Xin Wang Journal: Circ Res Date: 2003-02-13 Impact factor: 17.367
Authors: Frank M Davis; Debra L Rateri; Anju Balakrishnan; Deborah A Howatt; Dudley K Strickland; Selen C Muratoglu; Christopher M Haggerty; Brandon K Fornwalt; Lisa A Cassis; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2014-11-13 Impact factor: 8.311
Authors: Shohreh Maleki; Hanna M Björck; Valentina Paloschi; Sanela Kjellqvist; Lasse Folkersen; Veronica Jackson; Anders Franco-Cereceda; Per Eriksson Journal: Aorta (Stamford) Date: 2013-06-01
Authors: Kristin E Claflin; Jeremy A Sandgren; Allyn M Lambertz; Benjamin J Weidemann; Nicole K Littlejohn; Colin M L Burnett; Nicole A Pearson; Donald A Morgan; Katherine N Gibson-Corley; Kamal Rahmouni; Justin L Grobe Journal: J Clin Invest Date: 2017-03-06 Impact factor: 14.808
Authors: Xuan Zhang; Sean E Thatcher; Debra L Rateri; Dennis Bruemmer; Richard Charnigo; Alan Daugherty; Lisa A Cassis Journal: Circ Res Date: 2012-04-26 Impact factor: 17.367
Authors: Huiping Li; Eric T Weatherford; Deborah R Davis; Henry L Keen; Justin L Grobe; Alan Daugherty; Lisa A Cassis; Andrew M Allen; Curt D Sigmund Journal: Am J Physiol Regul Integr Comp Physiol Date: 2011-07-13 Impact factor: 3.619