Endothelin-1 but not angiotensin II contributes to functional aging in murine carotid arteries

Abstract

Aims: Aging is a major risk factor for carotid artery disease and stroke. Endothelin-1 (ET-1) and angiotensin II (Ang II) are important modifiers of vascular disease, partly through increased activity of NADPH oxidase and vasoconstrictor prostanoids. Since the renin-angiotensin and endothelin systems become activated with age, we hypothesized that aging affects NADPH oxidase- and prostanoid-dependent contractions to ET-1 and Ang II.

Main methods: Carotid artery rings of young (4 month-old) and old (24 month-old) C57BL6 mice were pretreated with the NO synthase inhibitor L-NAME to exclude differential effects of NO. Contractions to ET-1 and Ang II were determined in the presence and absence of the NADPH oxidase-selective inhibitor gp91ds-tat or the thromboxane-prostanoid receptor antagonist SQ 29,548. Gene expression of endothelin and angiotensin receptors was measured by qPCR.

Key findings: Aging reduced ET-1-induced contractions and diminished ETA but increased ETB receptor gene expression levels. Gp91ds-tat inhibited contractions to ET-1 in young and to a greater extent in old animals, whereas SQ 29,548 had no effect. Ang II-induced contractions were weak compared to ET-1 and unaffected by aging, gp91ds-tat, and SQ 29,548. Aging had also no effect on AT1A and AT1B receptor gene expression levels.

Significance: Aging in carotid arteries decreases ETA receptor gene expression and responsiveness to ET-1, which nevertheless becomes increasingly dependent upon NAPDH oxidase activity with age; responses to Ang II and gene expression of its receptors are however unaffected. These findings suggest that physiological aging differentially regulates functional responses to G protein-coupled receptor agonists and the signaling pathways associated with their activation.

Keywords: Age; Angiotensin II (PubChem CID: 172198); Artery; Atherosclerosis; Cyclooxygenase; Dementia; Endothelin-1 (PubChem CID: 16212950); GPCR; L-N(G)-nitroarginine methyl ester (PubChem CID: 39836); NADPH; Nox; Oxidative stress; Prostanoid; ROS; Reactive oxygen species; SQ 29,548 (PubChem CID: 5271); Stroke; Superoxide; Vascular; gp91ds-tat.