The Role of Vascular MR-Regulated Genes in Vascular Function and Disease

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The mineralocorticoid receptor (MR) is an aldosterone (Aldo)-activated receptor that regulates gene transcription (genomic) and cellular signaling (non-genomic) to control cell functions and regulate blood pressure (BP). MR activation is increased in resistant hypertension, obesity, heart failure and the elderly. Increased Aldo predicts high risk of myocardial infarction (MI) and stroke and MR antagonists are protective out of proportion to BP lowering, supporting kidney-independent mechanisms. MI and stroke are caused by rupture and thrombosis of inflamed atherosclerotic (athero) plaques. Women are protected from MI and stroke relative to men until menopause thereby implicating another hormone, estrogen (E2), while obese women with metabolic syndrome lose premenopausal protection with rising mortality in this growing demographic. We recently showed that MR in endothelial cells (EC) contributes to vascular inflammation in athero in male mice by inducing leukocyte recruitment to vessels and expression of ICAM1 and E-selectin (E-sel) and that this is prevented in females. We also showed that estrogen receptor alpha (ERa) interacts with the MR in ECs, blocking MR regulation of ICAM1 and that EC-MR-KO protects obese females from EC dysfunction. New data shows that ICAM1 expression is decreased in primary human ECs from females vs males and this is reversed in obese females; that EC-MR inhibits the non-genomic effect of E2 to increase nitric oxide (NO); and that myeloid (My)-MR-KO decreases plaque size and inflammation in ApoE-KO mice, leukocyte rolling by intravital microscopy (IVM), and macrophage expression of EC adhesion ligands. Based on these data, we propose to test the hypothesis that EC- and My-MR coordinate vascular inflammation in athero and that females are protected by genomic and non- genomic interactions between MR and ERa. To test this, we have created innovative reagents and methods including mice with EC-specific deletion of MR, ERa or both and myeloid-specific deletion of MR, each crossed to athero-prone genetic mouse models; a mesenteric IVM assay to test sex differences in leukocyte traficking; EC lines with ERa functional mutants; and a biobank of age matched male and female human aortic ECs. Using these tools we propose 2 specific aims, each using in vitro and in vivo approaches: SA1 explores the genomic and non-genomic mechanisms by which MR and ERa interact in ECs to regulate leukocyte recruitment and plaque inflammation and how this mediates sex differences; SA2 determines the role of My-MR in immune cell trafficking, plaque macrophage phenotype, and sex-differences in myeloid-T cell interactions. Using these innovative models, methods, and reagents tailored to study sex-differences, this proposal investigates the novel concept that EC- and My-MR coordinate vascular and immune cell responses to induce leukocyte recruitment and vascular inflammation in athero. Completion of the aims will identify mechanisms underlying increased cardiovascular (CV) risk in growing populations with elevated MR activity and for sex differences in CV disease.