Editors' ChoiceHypertension

A Mechanism of Interest as We Grow Older

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Science Translational Medicine  03 Oct 2012:
Vol. 4, Issue 154, pp. 154ec179
DOI: 10.1126/scitranslmed.3005014

Compared with previous generations, we are now living longer. But this comes with a grain of salt. Hypertension approaches 80% in octogenarians, meaning that, as we grow older, we have a greater risk of cardiovascular disease. Extrarenal expression of the mineralocorticoid receptor (MR) has been linked to blood pressure regulation. Setting out to explore this further, McCurley and colleagues now add the role of aging as a new dimension.

The authors first established a transgenic knockout mouse model in which MR depletion can be induced tissue-specifically in vascular smooth muscle cells (SMCs) after birth. Twenty-four-hour telemetry once per month over 10 months revealed that mice with SMCs lacking MR had decreased systolic blood pressure compared with their littermate controls. This effect on blood pressure increased with age. Furthermore, the vasoconstrictive response differed with age: “Old” mice (>9 months) with functional MR showed augmented vasoconstriction in mesenteric resistance arteries after stimulation with vasoconstrictors compared with the knockout mice. In contrast, “young” mice (3 to 4 months) did not show such a difference between the two groups. McCurley et al. showed that salt and mineralocorticoids similarly modulated blood pressure in both types of mice, suggesting that the MR is functional in the kidney of the knockout mice. This led the researchers to conclude that blood pressure is regulated by an extrarenal mechanism that involves the MR in vascular SMCs. From additional mechanistic studies, the authors suggest that the MR in SMC regulates an L-type calcium channel in vessels in an age-dependent fashion.

This new animal model lends not only insight into how age and mineralocorticoid receptor expression interact in blood pressure regulation, but will also serve as a platform to understand mechanisms of currently approved MR antagonists and those in development.

A. McCurley et al., Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat. Med. 18, 1429–1433 (2012). [PubMed]

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