Altered brain vascularization and transcriptional changes in embryos lacking ABCA1 support a role of cholesterol in brain angiogenesis

Introduction: Lipoproteins are the main lipid carriers in extracellular fluids and mediate the exchange of hydrophobic molecules between cells and their environment in animals, including cholesterol. Lipoprotein metabolism has been implicated in the regulation of angiogenesis, suggesting that cholesterol is important for this process, but a direct role for this lipid has not been unequivocally demonstrated, particularly in the central nervous system (CNS). Methods: Here, we used genetic and pharmacological models to address this issue in different models of CNS angiogenesis. Results: We show that inactivation of ABCA1, one of the main cholesterol efflux pumps, leads to altered brain vascularization and a longer angiogenic window, while inactivation of the bidirectional cholesterol transporter SR-B1 has no effect. These functional changes are accompanied by consistent transcriptomic changes in genes involved in cholesterol synthesis and angiogenesis. In support of the role of cholesterol, experimental reduction of this lipid in cultured brain endothelial cells leads to a transcriptomic signature showing the opposite direction in those genes. Discussion: These studies support a role for ABCA1 and cholesterol in regulating a trascriptional program governing angiogenesis in the brain.