The role of urotensin II in cardiovascular and renal physiology and diseases

Abstract

Urotensin II (U-II) is a cyclic neuropeptide that was first isolated from teleost fish some 35 years ago. Mammalian U-II is a powerful vasoconstrictor with a potency greater than that of endothelin-1.Nevertheless, unlike endothelin-1, which constricts all or nearly all vascular beds, the vasoactive effects of U-II are reported to be dependent both on the species and on the regional vascular bed examined. Typical regional variability occurs in the rat in which vasoconstriction to U-II is most robust in thoracic aorta proximal to the aortic arch and decreases gradually towards the distal peripheral arteries. As small peripheral arteries but not larger arteries such as the aorta play a major role in regulating peripheral resistance and consequent blood pressure as well as workload on the heart, doubts have been raised concerning the importance of this peptide in cardiovascular physiology. Moreover, an interaction between U-II and other endogenous vasoactive molecules may add a level of complexity to the vascular actions of U-II.On the other hand, recent experimental and clinical studies have revealed increased expression of U-II and urotensin receptor (UT receptor) in animals with experimentally induced myocardial infarction, heart failure, and in patients with hypertension, atherosclerosis, and diabetic nephropathy, which suggests a potential role for U-II in both cardiovascular and renal diseases. A series of peptidic and nonpeptidic UT receptor ligands have been shown to be effective in antagonizing the effects of U-II in the cardiorenal system. This article aims to review recent advances in our understanding of the physiology and pathophysiology of U-II with particular references to its role in cardiovascular health and disease.

Figure 1

Cellular localization of the U-II receptor GPR14 in the left ventricle of the rat (reproduced with permission from Gong et al. (2004)). (I) GPR14-positive signals visualized with the avidin–biotin–peroxidase complex (brown signals) in the left ventricle of the rats with light microscopy. The immunoreactive signals for GPR14 protein (arrow) are localized in the left ventricle (B). (A) Negative control of the left ventricle using the nonimmune rabbit IgG instead of the primary rabbit anti-GPR14 antibodies. A and B, bar=50 μm. (II) Photomicrographs show cellular localization of the GPR14 protein with immunofluorescence double staining in the left ventricle of the rats imaged with a confocal microscope. Sections were doubled stained with the endothelial cell type marker, MRC OX43 (A1, B1, and C1, green signal, arrow) and anti-GPR14 antibodies (A2, B2, and C2, red signal, arrow head). Panels A3, B3, and C3 are the superimpositions of A1 and A2, B1 and B2, and C1 and C2, respectively, showing that the cellular localization of GPR14 protein does not colocalize with the endothelial cells. Panels A4, B4, and C4 are the phase-contrast images of panels A1–A3, B1–B3, and C1–C3, respectively. Panels A1–A4, a double-stained left ventricular section showing GPR14 protein and the capillary endothelial cells. Panels B1–B4, a double-stained left ventricular section showing GPR14 protein, the capillary endothelial cells, and a cross-sectional intramyocardial coronary artery. Panels C1–C4, a feature view of a cross-sectional intramyocardial coronary artery. As can be taken from B3–B4 and C3–C4, the GPR14 protein (red signal, arrow head) is located neither on the endothelial cells (green signal, arrow) nor on the VSMC layer (open arrow head) of the intramyocardial coronary artery. A1–A4, B1–B4, bar=40 μm; C1–C4, bar=20 μm.

Figure 2

Changes in haemodynamics in anaesthetized cynomolgus monkeys after systemic administration of U-II (reproduced with permission from Zhu et al. 2004)). Urotensin II (U-II) produces a dose-dependent cardiovascular dysfunction in anaesthetized cynomolgus monkeys. Changes of hemodynamic parameters after systemic administration of 0.03 nmol/kg (↑) and 0.3 nmol/kg (↕) U-II (n=4) are seen. Bolus i.v. applications of U-II are indicated by the arrows. Heart rate (HR) (a), mean arterial blood pressure (MBP) (b), maximum first derivative of left ventricular pressure (dp/dt_max) (c), pulmonary pressure (d), coronary blood flow (e), and carotid blood flow (f). ^*P<0.05, ^**P<0.001 relative to baseline measurement before U-II administration (n=4). Values are means and vertical bars show s.d.

Figure 3

Schematic illustration of the suggested intracellular signalling mechanisms in VSMCs and the interaction between U-II and other vasoactive molecules.U-II, urotensin II; VSMCs, vascular smooth muscle cells; PKC, protein kinase C; MLC, myosin light chain; MLCK, myosin light-chain kinase; NADPH, nicotinamide adenosine dinucleotide phosphate; ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; Akt, protein kinase B; PAI-1, plasma plasminogen activator inhibitor-1; 5-HT, serotonin; moxLDL, mildly oxidized LDL; EDHF, endothelium-derived hyperpolarizing factor; NOS, nitric oxide synthase; NO, nitric oxide.