Electron Transfer Flavoprotein (ETF) alpha Controls Blood Vessel Development by Regulating Endothelial Mitochondrial Bioenergetics and Oxygen Consumption

While impairment of vascular homeostasis induced by hypercholesterolemia is the first step of cardiovascular diseases, the molecular mechanism behind such impairment is not well known. Here, we reported that high-cholesterol diet (HCD) induced defective vessel sprouting in zebrafish larvae. Electron transfer flavoprotein subunit alpha (ETF alpha) (encoded by the ETFA gene), a protein that mediates transfer of electrons from a series of mitochondrial flavoenzymes to the respiratory chain, was downregulated in HCD-fed zebrafish and in endothelial cells treated with oxidized low-density lipoprotein. Knockdown of ETF alpha with morpholino antisense oligonucleotides reproduced vascular sprouting defects in zebrafish larvae, while replenishing with exogeneous ETFA mRNA could successfully rescue these defects. ETFA knockdown in endothelial cells reduces cell migration, proliferation, and tube formation in vitro. Finally, knockdown of ETFA in endothelial cells also reduced fatty acid oxidation, oxygen consumption rate, and hypoxia-inducible factor-1 alpha (HIF1 alpha) protein levels. Taken together, we demonstrate that downregulation of ETF alpha is involved in hypercholesterolemia-induced defective vessel sprouting in zebrafish larvae via inhibition of endothelial proliferation and migration. The molecular mechanism behind this phenomenon is the decrease of HIF1 alpha induced by downregulation of ETF alpha in endothelial cells. This work suggests that disturbance of ETF alpha-mediated oxygen homeostasis is one of the mechanisms behind hypercholesterolemia-induced vascular dysfunction.