Relationship Between Hypertension and Atherosclerosis: From a Viewpoint of the Most Potent Vasoconstrictor Human Urotensin II

Abstract

Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in etiology of hypertension. In hypertensive patients, U-II induces vasoconstriction in forearm brachial artery infusion studies. Recent studies demonstrated elevated plasma U-II concentrations in patients with hypertension, diabetes mellitus, atherosclerosis, and coronary artery disease. U-II is expressed in endothelial cells, macrophages, macrophagederived foam cells, and myointimal and medial vascular smooth muscle cells (VSMCs) of atherosclerotic human coronary arteries. UT receptors are present in VSMCs of human coronary arteries, thoracic aorta and cardiac myocytes. Lymphocytes are the most active producers of U-II, whereas monocytes and macrophages are the major cell types expressing UT receptors, with relatively little receptor expression in foam cells, lymphocytes, and platelets. U-II accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages, and stimulates cell growth and up-regulates type 1 collagen expression in human endothelial cells. U-II also activates NADPH oxidase and plasminogen activator inhibitor-1 in human VSMCs, and stimulates VSMC proliferation with synergistic effects observed when combined with oxidized LDL, reactive oxygen species and serotonin. These findings suggest that U-II plays key roles in accelerating the development of atherosclerosis, and hence coronary artery disease.