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 α (ETFα) (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 ETFα 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-1α (HIF1α)
protein levels. Taken together, we demonstrate that downregulation of ETFα 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 HIF1α induced by downregulation of ETFα in endothelial cells. This work suggests that disturbance of ETFα-mediated
oxygen homeostasis is one of the mechanisms behind
hypercholesterolemia-induced vascular dysfunction.