Endothelial Cell–Specific Deficiency of Ang II Type 1a Receptors Attenuates Ang II–Induced Ascending Aortic Aneurysms in LDL Receptor −/− Mice
- 4 March 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 108 (5), 574-581
- https://doi.org/10.1161/circresaha.110.222844
Abstract
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 (AT1a) 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 AT1a receptor deficiency ablated Ang II–induced ascending AAs (P1a receptors on leukocytes, LDL receptor−/−×AT1a receptor+/+ or AT1a receptor−/− mice were irradiated and repopulated with bone marrow–derived cells isolated from either AT1a receptor+/+ or AT1a receptor−/− mice. Deficiency of AT1a receptors in bone marrow–derived cells had no effect on Ang II–induced ascending AAs. To determine the role of AT1a receptors on vascular wall cells, we developed AT1a receptor floxed mice with depletion on either smooth muscle or endothelial cells using Cre driven by either SM22 or Tek, respectively. AT1a 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 AT1a receptors that are expressed on endothelial cells.Keywords
This publication has 42 references indexed in Scilit:
- Aortic Adventitial Fibroblasts Participate in Angiotensin-Induced Vascular Wall Inflammation and RemodelingJournal of Vascular Research, 2010
- Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysmsJournal of Vascular Surgery, 2010
- 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic DiseaseCirculation, 2010
- Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− miceClinical Science, 2010
- Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFβ-Mediated Outflow Tract SeptationDevelopmental Cell, 2010
- Angiotensin II Induces a Region-Specific Hyperplasia of the Ascending Aorta Through Regulation of Inhibitor of Differentiation 3Circulation Research, 2010
- Angiotensin II Blockade and Aortic-Root Dilation in Marfan's SyndromeNew England Journal of Medicine, 2008
- Rationale and design of a randomized clinical trial of β-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndromeAmerican Heart Journal, 2007
- MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin IIHuman Molecular Genetics, 2007
- Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan SyndromeScience, 2006