5-Hydroxytryptamine–Induced Potentiation of Endothelin-1– and Norepinephrine-Induced Contraction Is Mitogen-Activated Protein Kinase Pathway Dependent

Abstract

Abstract-5-Hydroxytryptamine (5-HT)-induced arterial contraction depends on activation of the tyrosine kinasedependent extracellular signal-regulated mitogen-activated protein kinase (Erk MAPK) pathway. The importance of 5-HT in the control of peripheral resistance has been questioned because circulating free levels of 5-HT are low (in the nanomolar range). We tested the hypothesis that physiologically relevant concentrations of 5-HT potentiate arterial contraction in response to agonists proved to have importance in blood pressure maintenance (norepinephrine [NE] and endothelin-1 [ET-1]) in a tyrosine kinase-and an Erk MAPK-dependent manner. Strips of endothelium-denuded rat tail artery were used for the measurement of isometric force. The general tyrosine kinase inhibitor genistein (5 mol/L) and the inhibitor of MAPK/Erk kinase activation PD098059 (10 mol/L) shifted concentration-response curves to 5-HT (1ϫ10 Ϫ9 to 3ϫ10 Ϫ4 mol/L) rightward but did not shift concentration-response curves to NE or ET-1. In separate experiments, 5-HT (10 nmol/L) potentiated contraction in response to NE (20 nmol/L) by Ϸ200% to 300% and to ET-1 (0.3 and 1 nmol/L) by 640% and 180%, respectively. Genistein and PD098059 significantly (66% to 100%) reduced 5-HT-induced potentiation of both NE (20 nmol/L)-and ET-1 (0.3 and 1 nmol/L)-induced contraction. Thus, these data support the ability of low physiological concentrations of 5-HT to amplify arterial responses to hormones with bona fide effects on blood pressure in the novel manner of depending on a tyrosine kinase/Erk MAPK pathway. Although these findings were generated in large arteries, we speculate that they may be applicable to vascular functioning in the deoxycorticosterone acetate salt model of hypertension in which all 3 hormones, 5-HT, NE, and ET-1, have been implicated as causal factors. Key Words: norepinephrine Ⅲ endothelin Ⅲ protein kinases Ⅲ arteries Ⅲ hormones S ince its discovery in serum in 1948, 1 5-hydroxytryptamine (5-HT [serotonin]) has been of interest to the cardiovascular researcher. 5-HT has been implicated in numerous cardiovascular diseases; vascular reactivity to 5-HT is increased in arteries from animals with different forms of hypertension 2 and atherosclerosis. 3 However, it has been argued that 5-HT plays an insignificant role in the physiological control of blood vessel tone because uptake of 5-HT by platelets, adrenergic nerves, or both causes circulating levels of 5-HT to be low (estimated to be 15 to 120 nmol/L 4 ) and out of a range that can directly cause constriction. One manner by which physiological concentrations of 5-HT may exert an effect on vascular tone is through the potentiation of vascular contraction in response to other vasoactive substances.5-HT-stimulated potentiation of agonist-induced contraction has classically been studied in the tail artery of the rat. [5][6][7] Norepinephrine (NE) was one of the first agonists established to be potentiated by 5-HT. The list of hormones of which contraction can be potentiated by 5-HT has grow...

c-Jun N-terminal Kinase Contributes to Norepinephrine-Induced Contraction Through Phosphorylation of Caldesmon in Rat Aortic Smooth Muscle

“…To our knowledge, this is the first study to show that the JNK pathway contributes to the NEinduced contraction in rat vascular aortic smooth muscle. NE also increases the activity of ERK and p38 MAPK and induces contraction in vascular smooth muscle, which is inhibited by kinase inhibitors (15,16). These results indicate that, in rat aortic smooth muscle, JNK can be activated in parallel with isoforms of MAPK kinase, including ERK1 / 2 and p38 MAPK, and that this activation results in vascular contraction.…”

Oxidized Low-Density Lipoproteins Potentiate the Mitogenic Effect of 5-Hydroxytryptamine on Vascular Smooth Muscle Cells.

“…7,[21][22][23][24] In the present study, the mitogenic effect of 5-HT was significantly inhibited by the MAPK kinase inhibitor PD98059 but not by the intracellular antioxidant NAC. These findings suggest that the combined stimulation of the MAPK pathway by 5-HT and the redox-sensitive pathway by mox-LDL, ox-LDL, H 2 O 2 , LPC, or HNE may induce these synergistic interactions.…”

Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses

“…28) and a lack of understanding of the roles of 5-HT in the peripheral systems. One way by which physiological levels of 5-HT may have an effect on vascular tone is through the interaction with other vasoactive substances including ET-1, which could exacerbate the pathophysiological mechanisms.Evidence suggests that in the diabetic condition, there are elevated levels of 5-HT and ET-1, and they can both enhance each other's actions in vitro (17,19,28), but the physiological effect of this interaction, underlying molecular mechanisms, as well as their role in vascular remodeling in diabetes and vascular contraction are not yet completely elucidated. It is important to understand 5-HT/ET-1 interaction mechanisms that may accelerate the development cardiovascular complications such as hypertension and atherosclerosis, which commonly occur at an increased rate in diabetic patients compared with their age-matched controls.…”

“…5-HT has been associated with cardiovascular diseases such as atherosclerosis (10) and pulmonary hypertension (14), but it has been overlooked in some diseases because of its low circulating physiological levels (estimated to be in the 10 Ϫ9 M range; Ref. 28) and a lack of understanding of the roles of 5-HT in the peripheral systems. One way by which physiological levels of 5-HT may have an effect on vascular tone is through the interaction with other vasoactive substances including ET-1, which could exacerbate the pathophysiological mechanisms.…”

“…It is known that UO126, a MEK inhibitor, attenuated 5-HTinduced VSMC contraction ex vivo, suggesting the involvement of p42/44 MAPK pathway (23,29). Watts (28) demonstrated that 5-HT (10 Ϫ9 M) stimulated potentiation of vascular contraction in response to norepinephrine (NE) (10 Ϫ9 M) and ET-1(10 Ϫ9 M), which utilizes the p42/44 MAPK pathway and an undetermined tyrosine kinase. The mechanisms by which the p42/44 MAPK pathway participates in VSMC contraction were either due to de-activation of caldesmon (a calmodulin-binding protein, which activates actin-myosin ATPase; Ref.…”