Objective:
Low-density lipoprotein receptor related protein 1 (LRP1) deletion in smooth muscle cells (SMCs) during embryonic development augments angiotensin (Ang) II induced aneurysm formation in the ascending aorta and superior mesenteric artery. However, these studies have the potential confounding issue of LRP1 deficiency causing structural changes to arteries that may be the basis for this augmented pathology. The purpose of this study was to determine whether AngII-induced vascular changes were influenced when LRP1 deletion occurred in adult mice.
Methods and Results:
To temporally delete LRP1 in SMCs, we used a tamoxifen (tam)-dependent Cre (ERT2) recombinase under the control of a mouse smooth muscle cell actin (SMA) gene. SMA-ERT2-Cre +/0 males containing the ROSA26 reporter were bred to LRP1 floxed female mice to develop SMA-ERT2-Cre 0/0 and +/0 LRP1 x ROSA26 mice. SMC-specific deficiency of LRP1 was induced in mature mice via an injection of an ERT2 ligand, tam (1.5 mg/kg for 5 consecutive days). Non- transgenic littermates were also injected with tam. Tam injections in mice expressing ERT2-Cre led to uniform staining of β-galactosidase in medial SMCs of the aorta and arteries. LRP1 was deleted effectively from SMCs in ERT2-Cre expressing mice as demonstrated by Western blotting of aortic medial extracts. AngII (1,000 ng/kg/min) was infused via mini-osmotic pumps for 28 days into tam-injected mice that were either ERT2-Cre 0/0 or +/0. Consistent with constitutive SMC deletion, SMC LRP1 deletion in mature mice had no effect on dilation of the suprarenal aorta, but augmented expansion of the thoracic aorta and superior mesenteric artery in both male and female mice.
Conclusion:
Consistent with constitutive deletion, SMC LRP1 deletion in mature mice resulted in augmentation of AngII-induced thoracic aortic and superior mesenteric arterial aneurysms. These results demonstrate that undefined ligands acting at LRP1 are responsible for site-specific AngII-induced vascular pathologies.
Low-Density Lipoprotein Upregulates Low-Density Lipoprotein Receptor-Related Protein Expression in Vascular Smooth Muscle Cells
