NF-kappaB signaling mediates vascular smooth muscle endothelin type B receptor expression in resistance arteries

Jian-Pu Zheng, Yaping Zhang, Lars Edvinsson, Tord Hjalt, Cang-Bao Xu
European Journal of Pharmacology 2010 July 10, 637 (1): 148-54
Vascular smooth muscle cells (SMC) endothelin type B (ET(B)) receptor upregulation results in strong vasoconstriction and reduction of local blood flow. We hypothesizes that the underlying molecular mechanisms involve transcriptional factor nuclear factor-kappaB (NF-kappaB) pathway. ET(B) receptor upregulation and activation of NF-kappaB were studied at functional contraction (in vitro myograph), mRNA (real-time PCR), and protein (Western blot and immunocytochemistry) levels during organ culture of rat mesenteric arteries. Organ culture of the artery segments induced a time-dependent strong contractile response to sarafotoxin 6c in parallel with enhanced expression of ET(B) receptor mRNA and protein in the SMC. Western blot experiments demonstrated that phosphorylation of NF-kappaB p65 was time-dependently induced during organ culture starting at 1h. In addition, cytoplasmic IkB degradation occurred in parallel with nuclear NF-kappaB accumulation following organ culture. The enhanced expression of ET(B) receptor protein was apparent at 3h in the SMC and while enhanced ET(B) receptor-mediated contractions occurred first at 12h. The specific IkappaB inhibitors, IMD-0354 (N-(3,5-Bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide) and Wedelolactone (7-Methoxy-5,11,12-trihydroxycoumestan), abolished the organ culture induced ET(B) receptor upregulation. The intracellular NF-kappaB pathway is involved in the process of induced expression of vascular SMC ET(B) receptors.

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