Urotensin-II

U-II activates the UT receptor (UTSR), coupling through Gq to activate PLC-beta, generating IP3 and DAG. IP3 releases intracellular Ca2+ while DAG activates PKC, together triggering smooth muscle contraction. The UT receptor also signals through Gi (reducing cAMP) and activates MAPK/ERK cascades. In vitro, U-II produces sustained, concentration-dependent vasoconstriction in isolated arterial rings, particularly in primate and human vessels, where it is significantly more potent than ET-1.

In cardiomyocytes, UT receptor activation increases contractility acutely (positive inotropy) but promotes pathological hypertrophy chronically. U-II activates calcineurin/NFAT, MEK/ERK, and PI3K pathways in cardiomyocytes, driving protein synthesis and cell growth. It also promotes cardiac fibroblast activation and collagen deposition via TGF-beta upregulation, contributing to cardiac fibrosis in heart failure. These direct cardiac effects compound the afterload increase from systemic vasoconstriction.

UT receptor is expressed in the adrenal cortex, where U-II stimulates aldosterone secretion, contributing to sodium retention and volume expansion. In the kidney, U-II reduces GFR and renal plasma flow, acting as a potent renal vasoconstrictor. In metabolic contexts, U-II promotes insulin resistance by impairing insulin signaling in skeletal muscle and adipocytes. It also promotes endothelin-1 production, amplifying its own vasoconstrictor network.

Plasma U-II is elevated 2-3 fold in chronic heart failure and correlates with disease severity (NYHA class, BNP levels). Myocardial UT receptor expression is upregulated in failing human hearts. UT receptor antagonists (palosuran, GSK1440115) reduced cardiac fibrosis and improved hemodynamics in preclinical HF models. Phase II clinical trials of palosuran in HF showed modest but non-significant hemodynamic benefits, guiding design of next-generation UT antagonists.

U-II is produced in pulmonary vascular endothelium and is elevated in PAH patients. It promotes pulmonary vasoconstriction and vascular remodeling via UT receptor on pulmonary arterial smooth muscle. In hypertensive models, UT antagonism reduces blood pressure and vascular remodeling. The potency of U-II vasoconstriction in human pulmonary vessels makes it a compelling target in PAH where multiple vasoconstrictive pathways coexist.

Plasma U-II is elevated in type 2 diabetes and metabolic syndrome, correlating with insulin resistance independent of obesity. U-II impairs GLUT4 translocation in skeletal muscle and promotes adipogenesis via UT receptor. Whether these metabolic effects represent primary pathology or secondary phenomena from vascular disease is under study. UT antagonism improves insulin sensitivity in some rodent diabetes models.