Aging affects Kv7 channels and perivascular-adipose tissue-mediated vascular

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent K(v)7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography. We also performed bulk RNA sequencing and quantitative reverse transcription polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via K(v)7.3-5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, QO58 represents a novel tool for cardiovascular and hypertension research in aging.

Automated summary

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality, however, the detailed mechanisms are unclear. This study demonstrated that aging impairs the control of vascular tone via K(v)7 channels in perivascular adipose tissue, and identified QO58 as a novel pharmacological vasodilator for aging-related vascular dysfunction. Targeting inflammation and metabolism in perivascular adipose tissue may represent new approaches for restoring vascular function during aging.