Vascular Mineralocorticoid Receptors

Abstract

Vascular Mineralocorticoid Receptors 7 and impaired endothelium-dependent vascular relaxation which was both prevented by spironolactone. 28 Similar results were obtained in wild-type mice that received high-fat diet. 5 In line with this, high-fat diet–induced endothelial dysfunction and impaired vascular relaxation was restored by endothelial MR deletion. 1,6 This was accompanied by reduced oxidative stress and improved nitric oxide production in EC-MRKO mice 1,6 or after spironolactone treatment. 5 It has been demonstrated that ENaC is also expressed outside of the kidney in endothelial cells and contributes to endothelial cell and vascular stiffness. 29,30 ENaC expres-sion increases with age or in response to high-fat diet. 1,29 EC-MRKO 1 as well as treatment with spironolactone 29 or the ENaC inhibitor amiloride 29 prevented high-fat diet–induced or salt-induced endothelial cell stiffening. In a mouse model of Liddle syndrome, an inherited form of hypertension, aldoste-rone MR dependently increased endothelial ENaC expression and stiffness. 31 In summary, aldosterone via MR in vascular cells alters activity of ion channels, increases reactive oxygen species production, and impairs nitric oxide availability which might contribute to vascular stiffness and dysfunction (Figure). After endothelial injury or in the presence of risk factors, aldoste-rone predominantly exerts a contractile response, but this effect depends on the vascular bed and might involve differ-ent mechanisms. MR in endothelial cells contributes to arte-rial hypertension at pathological expression level, but it is dispensable at physiological expression level. MR in VSMC is essential for age-related or angiotensin II–related but not mineralocorticoid/salt-related hypertension. Interestingly, MR deletion from macrophages prevented the mineralocorticoid/ salt-induced increase in blood pressure, 32 suggesting that MR in different cell types are decisive for the response to different hypertensive stimuli. Aldosterone induces leukocyte infiltration, vascular inflam-mation, and fibrosis. 33 In part, this effect is mediated via MR in monocytes and macrophages, 32 but endothelial cells are a key regulator of leukocyte adhesion and transmigration. Accordingly, EC-MRKO prevented adverse cardiac remodel-ing in response to mineralocorticoid/salt-induced hyperten-sion in mice. 26,27 This was associated with a downregulation of intercellular cell adhesion molecule or vascular cell adhe-sion molecule in MR-deficient endothelial cells and less mac-rophage infiltration of the heart. 26,27 EC-MRKO 4 or treatment with spironolactone 34 protected from high-fat diet–induced macrophage accumulation, oxidative stress, cardiac fibrosis, and diastolic dysfunction. Together, these data show that the proinflammatory effect of aldosterone strongly depends on MR in endothelial cells. However, it has been shown earlier that aldosterone can rapidly induce vascular permeability by rearrangement of the actin cytoskeleton, suggesting that nontranscriptional signaling might as well be involved in the process. 35