Aging increases cytochrome P450 4A modulation of alpha(1)-adrenergic vasoconstriction

Dysfunction of the peripheral vasculature may underlie the aging-related increase in the risk of developing cardiovascular disease. In vascular smooth muscle cytochrome P450 4A (CYP4A) enzymes o-hydroxylize arachidonic acid to form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). CYP4A-dependent production of 20-HETE contributes to increased vasoconstriction noted in spontaneously hypertensive rats; however, the role of vascular CYP4A/20-HETE in aging is unknown. We hypothesized that aging increases CYP4A modulation of vasoconstriction in resistance arteries from male and female rats. In agreement with our hypothesis, CYP4A modulation of alpha1-adrenergic vasoconstriction was increased in aged (relative to young) male rats, and aged ovarian hormone-deficient (relative to aged intact and estrogen-replaced) female rats. Interestingly, CYP4A inhibition did not affect endothelin-1- or pressure-induced constriction. These data suggest that aging specifically increases alpha1-adrenergic-dependent activation of CYP4A/20-HETE. Further study may allow for the development of novel therapeutic interventions for the prevention of cardiovascular disease in aging men and women.