Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging

Abstract

Hypertension is nearly universal yet poorly controlled in the elderly despite proven benefits of intensive treatment. Mice lacking mineralocorticoid receptors in smooth muscle cells (SMC-MR-KO) are protected from rising blood pressure (BP) with aging, despite normal renal function. Vasoconstriction is attenuated in aged SMC-MR-KO mice, thus they were used to explore vascular mechanisms that may contribute to hypertension with aging. MicroRNA (miR) profiling identified miR-155 as the most down-regulated miR with vascular aging in MR-intact but not SMC-MR-KO mice. The aging-associated decrease in miR-155 in mesenteric resistance vessels was associated with increased mRNA abundance of MR and of predicted miR-155 targets Cav1.2 (L-type calcium channel (LTCC) subunit) and angiotensin type-1 receptor (AgtR1). SMC-MR-KO mice lacked these aging-associated vascular gene expression changes. In HEK293 cells, MR repressed miR-155 promoter activity. In cultured SMCs, miR-155 decreased Cav1.2 and AgtR1 mRNA. Compared to MR-intact littermates, aged SMC-MR-KO mice had decreased systolic BP, myogenic tone, SMC LTCC current, mesenteric vessel calcium influx, LTCC-induced vasoconstriction and angiotensin II-induced vasoconstriction and oxidative stress. Restoration of miR-155 specifically in SMCs of aged MR-intact mice decreased Cav1.2 and AgtR1 mRNA and attenuated LTCC-mediated and angiotensin II-induced vasoconstriction and oxidative stress. Finally, in a trial of MR blockade in elderly humans, changes in serum miR-155 predicted the BP treatment response. Thus, SMC-MR regulation of miR-155, Cav1.2 and AgtR1 impacts vasoconstriction with aging. This novel mechanism identifies potential new treatment strategies and biomarkers to improve and individualize antihypertensive therapy in the elderly.

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…This effect is mediated by reduced myogenic tone, vasoconstriction and oxidative stress. 21,22 Moreover, the vascular stiffness and fibrosis associated with ageing are prevented in mice deficient of MR in VSMCs. 23 MR activation has been shown to promote the expression of genes involved in MR-dependent vascular remodelling and calcification in VSMCs, such as collagens I and III, the integrin alpha-5 subunit, IL-16 and cytotoxic T-lymphocyte antigen-4 for vascular remodelling and genes associated with vascular calcification, such as alkaline phosphatase, parathyroid hormone receptor-2 and bone morphogenetic protein-2.…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

“…2017), interaction between MR and other transcription factors such as NFkB and AP-1 (Fiebeler et al . 2001), non-genomic activation of signaling pathways that impinge on gene regulation, and suppression of miR expression by MR resulting in up-regulation of vascular miR target genes (DuPont et al . 2016).…”

“…Further studies showed that SMC-MR-KO mice generated less spontaneous vascular myogenic tone, suggesting that SMC-MR contributes to blood pressure control via alterations in vasoconstriction by changes in vascular L-type calcium channel expression and function (McCurley et al . 2012 a , DuPont et al . 2016).…”

Mineralocorticoid Receptor in Calcium Handling of Vascular Smooth Muscle Cells

“…However, this phenomenon seems indeed to be an age-dependent effect, since a latter study did not validate, at protein level, the downregulation of Ca v 1.2 in aortas from young VSMC-MR-KO mice [102]. Furthermore, during the aging process, MR expression increases in resistance vessels along with a decline in the microRNA (miR)-155 abundance, suggesting that Ca v 1.2 is a downstream target of miR-155 regulation [103].…”