Smooth Muscle Cell Mineralocorticoid Receptors Are Necessary for Cardiovascular Fibrosis with Aging

Abstract

Vascular aging involves fibrosis leading to stiffening of the vascular wall, an independent predictor of adverse cardiovascular events. Mineralocorticoid receptors (MR) are expressed in vascular smooth muscle cells (SMC) and MR signaling has been implicated in the regulation of cardiovascular fibrosis but has not been explored in cardiovascular aging. We previously demonstrated that aged mice lacking MR in SMCs (SMC‐MR‐KO) have lower blood pressure and reduced responsiveness to angiotensin II. The aim of this study was to investigate the role of SMC‐MR in cardiovascular structural and functional changes with aging and to explore mechanisms by which SMC‐MR contributes to vascular aging by modulating global vascular gene expression in mice. Vascular and cardiac fibrosis, aortic pulse wave velocity (PWV), cardiac echocardiography, intra‐cardiac pressure‐volume loops, and endurance exercise capacity were assessed in 3, 12 and 18 month‐old male MR‐intact and SMC‐MR‐KO mice. Vascular fibrosis in aortas, carotid arteries, and renal arterioles and aortic stiffness increased with aging in MR‐intact mice. Importantly, these aging‐induced increases were attenuated in SMC‐MR‐KO mice. Cardiac hypertrophy, wall thickness, fibrosis and stiffness increased and cardiac function and endurance exercise capacity decreased with aging in MR‐intact mice. Aging‐induced changes in cardiac hypertrophy, wall thickness and function were unaffected by the absence of SMC‐MR, however, SMC‐MR‐KO mice were protected from the aging‐induced increases in cardiac fibrosis and stiffness and the decrease in endurance exercise capacity. There was a significant correlation between aortic PWV and end‐systolic pressure volume relationship, suggesting that the changes in cardiac systolic stiffness are likely secondary to changes in aortic stiffness with aging. Renal fibrosis increased with aging but this increase was independent of the presence of SMC‐MR. To explore the mechanism by which SMC‐MR contributes to vascular fibrosis and stiffness with aging, we characterized global gene expression profiles in aortas from 3 and 12 month‐old MR‐intact and SMC‐MR‐KO mice. 552 and 477 genes were differentially expressed with aging in aortas from MR‐intact and SMC‐MR‐KO, respectively. Only 79 genes were differentially expressed with aging in both MR‐intact and SMC‐MO‐KO mice. Pathway analysis revealed that changes in cardiovascular development pathways with aging are predicted to act in opposing directions in SMC‐MR‐KO mice compared to MR intact mice. We also identified a network of fibrosis‐related genes that are down‐regulated with aging in SMC‐MR‐KO mice, providing a possible mechanism for the reduced vascular fibrosis with aging in SMC‐MR‐KO mice. Our findings provide evidence that SMC‐MR plays a role in aging‐induced increase in vascular fibrosis that contributes to cardiovascular tissue stiffening and dysfunction with aging. Further studies are underway to treat aged mice with MR antagonist to attempt to reverse the aging phenotype.Support or Funding InformationNIH/NHLBI R01 HL119290 and AHA EIA18290005