Endothelial cell-specific deficiency of ang II type 1a receptors attenuates ang II-induced ascending aortic aneurysms in LDL Receptor-/- mice

Debra L. Rateri, Jessica J. Moorleghen, Anju Balakrishnan, A. Phillip Owens, Deborah A. Howatt, Venkateswaran Subramanian, Aruna Poduri, Richard Charnigo, Lisa A. Cassis, Alan Daugherty

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

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 (P<0.001). To determine the role of AT1a receptors on leukocytes, LDL receptor×AT 1a 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.

Original languageEnglish
Pages (from-to)574-581
Number of pages8
JournalCirculation Research
Volume108
Issue number5
DOIs
StatePublished - Mar 4 2011

Keywords

  • AT receptor
  • Tek-cre
  • angiotensin II
  • ascending aneurysm

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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