Liver X Receptor Activation Reduces Angiogenesis by Impairing Lipid Raft Localization and Signaling of Vascular Endothelial Growth Factor Receptor-2

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 9; pp. 2280 - 2288
• Main Authors: Noghero, Alessio, Perino, Alessia, Seano, Giorgio, Saglio, Elisa, Sasso, Giuseppe Lo, Veglio, Franco, Primo, Luca, Hirsch, Emilio, Bussolino, Federico, Morello, Fulvio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-09-2012; Lippincott Williams & Wilkins
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Atherosclerosis (general aspects, experimental research); Benzoates - pharmacology; Benzylamines - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Carcinoma, Lewis Lung - blood supply; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Cardiology. Vascular system; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Cholesterol - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Female; Fundamental and applied biological sciences. Psychology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hydrocarbons, Fluorinated - pharmacology; Liver X Receptors; Medical sciences; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic - drug effects; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - deficiency; Orphan Nuclear Receptors - genetics; Orphan Nuclear Receptors - metabolism; Phosphorylation; RNA Interference; Signal Transduction - drug effects; Sulfonamides - pharmacology; Time Factors; Transfection; Tumor Burden; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vertebrates: cardiovascular system; lipid rafts; Digestive system; Liver; Lipids; Cardiovascular disease; Cholesterol; Vascular disease; Angiogenesis; Growth factor receptor; vascular endothelial growth factor; Atherosclerosis; liver X receptor; Growth factor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.112.250621

OBJECTIVE—Liver X receptors (LXRα, LXRβ) are master regulators of cholesterol homeostasis. In the endothelium, perturbations of cell cholesterol have an impact on fundamental processes. We, therefore, assessed the effects of LXR activation on endothelial functions related to angiogenesis in vitro and in vivo.
METHODS AND RESULTS—LXR agonists (T0901317, GW3965) blunted migration, tubulogenesis, and proliferation of human umbilical vein endothelial cells. By affecting endothelial cholesterol homeostasis, LXR activation impaired the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts/caveolae and led to defective phosphorylation and downstream signaling of vascular endothelial growth factor receptor-2 upon vascular endothelial growth factor-A stimulation. Consistently, the antiangiogenic actions of LXR agonists could be prevented by coadministration of exogenous cholesterol. LXR agonists reduced endothelial sprouting from wild-type but not from LXRα/LXRβ knockout aortas and blunted the vascularization of implanted angioreactors in vivo. Furthermore, T0901317 reduced the growth of Lewis lung carcinoma grafts in mice by impairing angiogenesis.
CONCLUSION—Pharmacological activation of endothelial LXRs reduces angiogenesis by restraining cholesterol-dependent vascular endothelial growth factor receptor-2 compartmentation and signaling. Thus, administration of LXR agonists could exert therapeutic effects in pathological conditions characterized by uncontrolled angiogenesis.