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

• DOI: 10.1161/atvbaha.112.250621
• Publication Date: 2012-06-22T16:25:08Z
• Authors: Alessio Noghero; Alessia Perino; Giorgio Seano; Elisa Saglio; Giuseppe Lo Sasso; Franco Veglio; Luca Primo; Emilio Hirsch; Federico Bussolino; Fulvio Morello
• Keywords: Mice, Knockout; 0301 basic medicine; Benzylamines; Hydrocarbons, Fluorinated; angiogenesis; cholesterol; lipid rafts; liver X receptor; vascular endothelial growth factor; Angiogenesis Inhibitors; Animals; Aorta, Thoracic; Benzoates; Benzylamines; Carcinoma, Lewis Lung; Cell Movement; Cell Proliferation; Cells, Cultured; Cholesterol; Endothelial Cells; Female; Human Umbilical Vein Endothelial Cells; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; Membrane Microdomains; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Orphan Nuclear Receptors; Phosphorylation; RNA Interference; Signal Transduction; Sulfonamides; Time Factors; Transfection; Tumor Burden; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Cardiology and Cardiovascular Medicine; Endothelial Cells; Angiogenesis Inhibitors; Aorta, Thoracic; Benzoates; Mice, Inbred C57BL; Carcinoma, Lewis Lung; Mice; 03 medical and health sciences; Cholesterol; Membrane Microdomains; Cell Movement; Human Umbilical Vein Endothelial Cells; Animals; Humans; Female; Cells, Cultured; Cell Proliferation; Liver X Receptors

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.