Tail Pressure Factors Ii And Angiotensin Ii On The Vasoconstriction Synergy And Its Signaling Pathways

Urotensin II (U-II) was the first isopeptides characterized from the terminal organ of the urophusis and has been demonstrated to the most potent vasoconstrictor identified to date. The vasoconstrictor activity of U-II is dependent upon, not only the anatomical origin of the vessel studied, but also the species from which it was isolated and has differential roles in cardiovascular physiology and pathophysiology. The expression of U-II has been shown to be up-regulated in the plasma of patients with congestive heart failure as well as in infrated heart of the rat and hypertension and atherosclerotic lesions of human aorta. In cardiovascular disease, many vasocontrictors such as angiotensin II (Ang II), endothelin (ET-1) catecholamines have shown to be up-regulated, which may consequently modulate the vasoactive effect of U-II. Recently, synergistic effects of U-II with mildly oxidized LDL and serotonin on vascular smooth muscle cell proliferation has been reported. And this may explain the relatively rapid progression of atherosclerosis in patients with hypertension and hypercholesterolemia. In conclusion, exploration of interactive effect and mechanism between U-II and other vasoactive peptides may have far-reaching influence on our understanding of the mechanism of cardiovascular remodeling and the development of new anti-remodeling agents.In present study, we observed a novel synergistic interaction between U-II and Ang II in organ bath study. We use low dose of U-II and Ang II which induced only a little response in endothelium-denuded rat thoracic aorta and explore the mechanism.We found that co-administration of U-II (1 nM) and Ang II (2 nM) exerted a significant contractile effect which was abrogated by either PKC inhibitor chelerythrine, U-II receptor ligand inhibitor urantide, or Ang II type 1 receptor antagonist Losartan. We further observed the synergistic effect was paralleled with increase PKC activity as well as phosphorylation of PKC isoforms alpha /beta II and MLC, whilst U-II and Ang II administered alone at these concentrations has no effect. U-II alone caused a dose-dependent increase in phosphorylation of PKC isoforms alpha /beta II and theta and MLC and PKC activity. U-II-induced constriction of aorta and MLC and PKC isoform phosphorylation were prevented by urantide and chelrythrine.To further analyze the PKC-sensitive component, hU-II-induced contraction was measured in the presence of the voltage-gated Ca²⁺ channel inhibitorMethoxyverapamil/thapsigargin(TSG/D600) suppress the agonist-induced rise in [Ca²⁺]_i. The TSG/D600-resistant component of hU-II-induced contraction was dose-dependently inhibited by chelerythrine. Moreover, U-II elicited a greater constrictor response of aortic rings isolated from 17-week-SHR (endothelium-denuded) compared to WKY rats. The contractile response to U-II was different in different pathophysiological disease. Moreover, we investigated the effect and mechanism in rat and human arterial vascular smooth muscle cells.Because U-II had important effect in cardiovascular disease, we investigated GPR 14 receptor (now named UT receptor) in the ventricle of normal rat heart with immunoprecipitation and Western blot analysis and the effects on cardiomyocytes. We also constructed recombinant adenovirus vector which containing U-II receptor (GPR14) and made a basis for further research.In conclusion, we first investigated U-II interacts synergistally with Ang II through a PKC-dependent cross-talk of the intracellular signaling pathways of these two peptides. Alpha /betaII may be the PKC isoform involved in the synergistic interaction between U-II and Ang II. Morover, different PKC isoforms contributes to the transient or long-lasting effect of hU-II-induced vasoconstriction. The contractile effect of U-II is more pronounced in arteries of SHR compared to WKY rats. This will have far-reaching influence on our understanding of the mechanism and effect of U-II in cardiovascular disease.