Aging-Associated Vascular Phenotype in Mutant Mice With Low Levels of BubR1

Abstract

Aging is a major risk for stroke and a highly complex biological process believed to involve multiple mechanisms. Mutant mice that express low levels of the spindle assembly checkpoint protein BubR1 are known to develop several aging-associated phenotypes at a very young age, including cataracts, lordokyphosis, loss of subcutaneous fat, and impaired wound healing. However, whether BubR1 acts to prevent vascular aging has not yet been established. The present study was designed to investigate the vascular phenotype of mutant mice with low levels of BubR1. Morphological, functional, and biochemical analyses were performed on aortas and carotid arteries of 3- to 5-month-old BubR1 mutant mice and wild-type littermates. Arterial wall thickness and inner diameter were significantly reduced in BubR1 mutant mice. Arterial walls of BubR1 mutant mice had low numbers of medial smooth muscle cells. Masson trichrome staining showed profound fibrosis in arterial walls of BubR1 mutant. In agreement with these morphological changes, functional analysis of pressurized isolated carotid arteries of BubR1 mutant mice demonstrated reduced elastic properties. Endothelium-dependent relaxations to acetylcholine and endothelium-independent relaxations to the nitric oxide donor DEA-NONOate were significantly reduced in carotid arteries of BubR1 mutant mice. Furthermore, enzymatic activity of nitric oxide synthase and levels of cyclic GMP were significantly reduced in aortas of mutant mice, but production of superoxide anions was significantly increased. These findings demonstrate that BubR1 insufficiency in mice results in phenotypic changes reminiscent of vascular aging in humans and suggest a role for BubR1 in suppressing the vascular aging process.