Smooth Muscle Mineralocorticoid Receptor in Obesity-Induced Vascular Stiffness

Tufts Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

Obesity impacts 42% of US adults with greater prevalence in women. Obesity is associated with increased risk of cardiovascular (CV) disease. Elevated body mass index strongly correlates with large vessel vascular stiffness which increases cardiac work and damages small vessels, thereby also correlating with risk of hypertension, heart attack, stroke and heart failure. The associations of obesity and vascular stiffness with adverse CV outcomes are steeper in woman than men, suggesting sex-specific mechanisms that may require precision targeting strategies. This competitive renewal application proposes to explore the role of the mineralocorticoid receptor (MR) in vascular smooth muscle cells (SMC) in sex-specific mechanisms of obesity-induced vascular stiffness. The MR is the aldosterone-activated transcription factor that regulates blood pressure in the kidney. Our published data from the prior cycle implicated SMC-MR in vascular aging. Our new preliminary data reveals that SMC-MR expression is increased in the aorta of obese versus lean mice and in primary human aortic (HA)SMCs from obese vs lean human donors. We also show that mice with SMC-specific MR deletion (SMC- MR-KO) are protected from high fat diet (HFD)-induced aortic stiffening in both sexes, but by sexually dimorphic mechanisms. This proposal tests the hypothesis that obesity causes perivascular adipose tissue (PVAT)-derived oxidative stress in females whichinduces SMC HIF1α and the MR-1α isoform while in males, PVAT inflammation predominates and induces SMC NFκB raising both MR isoforms, and that these sexually dimorphic mechanisms drive global sex-specific changes in vascular stiffness genes resulting in vascular stiffening and cardiac dysfunction in obesity. Using innovative approaches including a novel mouse with CRISPR/Cas9-mediated knock-in of an HA tag in the MR genomic locus, a mouse with SMC-specific inducible oxidative stress, spatial transcriptomics of single mouse aortas with perivascular adipose tissue (PVAT) combined this ChIP-sequencing, multiplexed RNA-FISH, and atomic force microscopy (AFM) combined with confocal microscopy, we propose 3 Aims: SA1-Determine sex-specific mechanisms bywhich MR is induced in SMC by obesity; SA2-Identify sexually dimorphic mechanisms of obesity-induced vascular stiffening and its impact on CV function; and SA3-Explore sex-specific, SMC-MR-dependent mechanisms controlling global aortic gene expression in obesity. Each aim uses primary human aortic SMCs from lean males and females (BMI<=25) to those with obesity (BMI>=30) and male and female mouse models with diet-induced obesity. Completion of the aims will determine novel sex- specific mechanisms driving obesity-associated vascular stiffness and end organ dysfunction, implicating SMC- MR by using innovative approaches. The long-term goal is to determine sex-specific precision medicine strategies, including FDA approved MR antagonists, to mitigate obesity-induced vascular stiffening and the myriad of adverse consequences in order to ameliorate the expected rise in CV disease as the growing obese population ages.