Abstract 101: LRP1 Deficiency in Vascular Smooth Muscle Cells Augments Development of Angiotensin II-Induced Ascending Aortic and Superior Mesenteric Artery Aneurysms
Introduction and Objective: LDL receptor related protein 1 (LRP1) is an endocytic receptor highly expressed in vascular smooth muscle cells that maintains the integrity of the vessel wall. In addition, a recent genome-wide association study implicated LRP1 as a susceptibility locus for human aortic aneurysms. Chronic angiotensin II (AngII) infusion in mice leads to formation of ascending and abdominal aortic aneurysms (AAs). The purpose of this study was to define whether deficiency of LRP1 in vascular smooth muscle cells alters development of either AngII-induced ascending or abdominal AAs.
Methods and Results: Eight week old male mice with a smooth muscle cell specific-deficiency in LRP1 (smLRP1-/-) were generated by crossing sm22 promoter-driven Cre transgenic mice with lrp1 flox/flox mice. Littermates not expressing Cre were used as controls (smLRP1+/+). Mice were randomized into 4 groups: smLRP1+/+ saline infusion, smLRP1+/+ AngII infusion (1,000 ng/kg/min), smLRP1-/- saline infusion, and smLRP1-/- AngII infusion for 4 weeks. At baseline, there was no difference in aortic diameter in smLRP1-/- vs smLRP1+/+ mice. Following 4 weeks of infusion, smLRP1-/- exacerbated AngII-induced ascending AA development (growth of ascending aortic diameter: smLRP1+/+ saline: 0.10 ± 0.03 mm; smLRP1-/- saline 0.09 ± 0.03 mm; smLRP1+/+ AngII: 0.20 ± 0.03 mm; smLRP1-/- AngII: 0.50 ± 0.10 mm, P<0.01). In addition, AngII-infused smLRP1-/- mice exhibited superior mesenteric artery dilation that was quantified by a 7T Bruker ClinScan magnetic resonance imager (smLRP1+/+ saline: 0.41 ± 0.01 mm; smLRP1-/- saline 0.49 ± 0.05 mm; smLRP1+/+ AngII: 0.36 ± 0.02 mm; smLRP1-/- AngII: 1.14 ± 0.34 mm, P<0.02). Immunostaining of ascending aortas in smLRP1-/- mice revealed increased elastin breaks (P<0.05) without macrophage infiltration. The superior mesenteric artery displayed elevated intima and media macrophage infiltration (P<0.05). Interestingly, smLRP1-/- did not augment AngII-induced abdominal AA development.
Conclusion: LRP1 deficiency in vascular smooth muscle cells exacerbates development of AngII-induced ascending aortic and superior mesenteric artery aneurysms, without contributing to development of abdominal aortic aneurysms.
Author Disclosures: F. Davis: None. C.M. Haggerty: None. D.L. Rateri: None. D.A. Howatt: None. A. Balakrishnan: None. J.J. Moorleghen: None. B.K. Fornwalt: None. D. Strickland: None. A. Daugherty: None.
- © 2014 by American Heart Association, Inc.