Urotensin II Enhances Advanced Aortic Atherosclerosis Formation and Delays Plaque Regression in Hyperlipidemic Rabbits

Abstract

Accumulated evidence shows that elevated urotensin II (UII) levels are associated with cardiovascular diseases. However, the role of UII in the initiation, progression, and regression of atherosclerosis remains to be verified. Different stages of atherosclerosis were induced in rabbits by a 0.3% high cholesterol diet (HCD) feeding, and either UII (5.4 μg/kg/h) or saline was chronically infused via osmotic mini-pumps. UII promoted atherosclerotic fatty streak formation in ovariectomized female rabbits (34% increase in gross lesion and 93% increase in microscopic lesion), and in male rabbits (39% increase in gross lesion). UII infusion significantly increased the plaque size of the carotid and subclavian arteries (69% increase over the control). In addition, UII infusion significantly enhanced the development of coronary lesions by increasing plaque size and lumen stenosis. Histopathological analysis revealed that aortic lesions in the UII group were characterized by increasing lesional macrophages, lipid deposition, and intra-plaque neovessel formation. UII infusion also significantly delayed the regression of atherosclerosis in rabbits by increasing the intra-plaque macrophage ratio. Furthermore, UII treatment led to a significant increase in NOX2 and HIF-1α/VEGF-A expression accompanied by increased reactive oxygen species levels in cultured macrophages. Tubule formation assays showed that UII exerted a pro-angiogenic effect in cultured endothelial cell lines and this effect was partly inhibited by urantide, a UII receptor antagonist. These findings suggest that UII can accelerate aortic and coronary plaque formation and enhance aortic plaque vulnerability, but delay the regression of atherosclerosis. The role of UII on angiogenesis in the lesion may be involved in complex plaque development.

Urotensin II promotes the proliferation and secretion of vascular endothelial growth factor in rat dermal papilla cells by activating the Wnt-β-catenin signaling pathway

“…It has been reported that rabbit macrophages and human vascular endothelial cells were induced to secrete VEGF by U II, 18,19 suggesting that U II is likely to be an important factor in promoting VEGF secretion from DPCs. To confirm the effect of U II on the VEGF secretion from DPCs, the concentration of VEGF in the supernatant of DPCs cultured medium was detected by ELISA.…”

Inquiring about the link between urotensin-II and coronary collateral development in coronary artery patients with and without diabetes

“…U-II expression is often found to be increased in atherosclerotic lesions in the coronary and carotid arteries and aorta. 16 Accordingly, it was suggested that elevated expression of U-II leads to vascular smooth muscle proliferation, accelerating the development of atherosclerotic plaque. In addition, it was shown that locally released U-II leads to coronary vasoconstriction and myocardial ischemia.…”