Aging Increases Cytochrome P450 4A Modulation of α1-Adrenergic Vasoconstriction in Mesenteric Arteries

Abstract

Aging is associated with peripheral vascular dysfunction. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE acts as an intracellular messenger to modulate vasoconstriction induced by various agonists, including the alpha1-adrenergic agonist phenylephrine (PE) and endothelin-1 (ET-1). Eicosanoids produced by CYP4A contribute to the elevated vascular tone in hypertension, but the effects of advanced age on CYP4A modulation of vasoconstriction are unknown. Mesenteric arteries were isolated from young (3 to 4 months) and aged (17 to 18 months) Sprague-Dawley rats. Vasoconstriction was induced with PE or ET-1 in the absence or presence of the CYP4A inhibitor DDMS and/or the ETA inhibitor BQ123. CYP4A inhibition with DDMS significantly reduced PE sensitivity in aged rats, but it had no effect in young. Furthermore, in aged rats only, ETA inhibition reduced PE sensitivity while combined inhibition of CYP4A and ETA had no additional effect, suggesting that the pathways work in concert in aging. Exogenous ET-1 constriction was not altered by DDMS in young or aged rats. Overall, our data indicate that aging increases the contribution of CYP4A to alpha1-adrenergic vasoconstriction in systemic arteries. Understanding aging-related changes in vascular function is important for development of novel targets for the prevention of cardiovascular disease.