BK_Ca channel activity and vascular contractility alterations with hypertension and aging via β1 subunit promoter methylation in mesenteric arteries.

Promoter methylation is a key mechanism in the epigenetic reprogramming of gene expression patterns. Here, we investigated the contribution of DNA methylation and the associated expression and function of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel in mesenteric arteries when hypertension was superimposed on aging. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) at young (12 weeks), adult (36 weeks) and old (64 weeks) life stages were used. BK_Ca channel currents, BK_Ca channel activity in regulating vascular tone, and BK_Ca channel β1 subunit (BKβ1) function and expression were greater in mesenteric arteries from SHR than from age-matched WKY controls. Consistently, hypertension decreased CpG methylation of the BKβ1 promoter at all ages. Furthermore, aging triggered an increase in BKβ1 promoter methylation in both old WKY and SHR, with concomitant suppression of the β1 subunit and BK_Ca channel activity. Aging enhanced β1 gene promoter methylation and subunit expression without changing BK_Ca channel function between young and adult WKY animals. In contrast, aging did not alter CpG methylation but facilitated BK_Ca channel currents and upregulated BKβ1 expression and function in adult SHR. Taken together, our results provide compelling evidence that hypertension and aging exert opposing effects on DNA methylation at BKβ1 promoter, subsequently resulting in different β1 expression levels and functional modulation of mesenteric arterial contractility. Such information is useful in revealing the epigenetic regulation of BK_Ca channel function in vascular smooth muscle and in comprehensively understanding the molecular mechanisms in vascular physiology and pathophysiology.

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