GAA deficiency promotes angiogenesis through upregulation of Rac1 induced by autophagy disorder.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is vital for vertebrate development and adult homeostasis. Acid α-glucosidase (GAA) is a glycoside hydrolase involved in the lysosomal breakdown of glycogen. Our previous study showed that GAA was highly expressed in mouse pulmonary veins. While whether GAA was involved in angiogenesis remained largely unknown, thus, we performed knockdown experiments both in vivo and in vitro and endothelial cell function experiments to clarify this concern point. We identified that GAA expressed widely at different levels during zebrafish embryonic development and GAA morphants showed excessive angiogenesis of ISV at later stage. In GAA knockdown HUVECs, the migration and tube formation capacity were increased, resulted from the formation of large lamellipodia-like protrusions at the edge of cells. By analyzing autophagic flux, we found that autophagy disorder was the mechanism of GAA knockdown-induced excessive angiogenesis. The block of autophagic flux caused upregulation of Rac1, a small GTPase, and the latter promoted excessive sprouts in zebrafish and enhanced angiogenic behavior in HUVECs. In addition, overexpression of transcription factor E3, a master regulator of autophagy, rescued upregulation of RAC1 and enhanced angiogenic function in GAA-knockdown HUVECs. Also, inhibition of Rac1 partly restored enhanced angiogenic function in GAA-knockdown HUVECs. Taken together, our study firstly reported a novel function of GAA in angiogenesis which is mediated by upregulation of Rac1 induced by autophagy disorder. • GAA deficiency promotes excessive angiogenesis in zebrafish intersegmental vessels. • GAA deficiency enhances migration and tube formation of human umbilical vein endothelial cells. • GAA deficiency mediated the excessive angiogenesis through autophagy buildup and subsequent upregulation of RAC1. • Regulation of autophagy and inhibition of RAC1 restored the GAA deficiency-mediated excessive angiogenesis. [ABSTRACT FROM AUTHOR]