Abstract WP154: Estrogen Modulates Serotonin-induced Vasoconstriction Through Tyrisine Kinase Inhibition

Abstract

Earlier onset of menopause may influence the risk of stroke. However, hormone therapy, estrogen, alone or with a progestogen, increases stroke risk. Thus, it is needed to clarify whether estrogens prevent or promote vasomotor symptoms, as well as the mechanism(s) involved. Recent study showed that serotonin enhancing drugs, including antidepressants, migraine therapies and diet pills, can trigger a stroke via vasoconstriction. In this study, we examined the modulatory mechanisms of estrogen in serotonin -induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17β-estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aorta strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes were not mediated by estrogen receptor. Patch clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which is significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK239T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerted vasodilatory effects on serotonin-precontracted artery via Src, implying a critical role of estrogen in prevention of vascular hyperreactivity to serotonin.