The expression and role of transcription factor Sox17 in angiogenesis

Abstract

Vessel formation is one of the crucial step during development and tumor growth due to the need of nutrition, oxygen supply and clearance of the waste product from every single cell in the tissue. Angiogenesis is a new vessel outgrowth from pre-existing vasculatures, and the most initial step of this is tip and stalk cell specification. Tip cells are highly mobile, non-proliferative cells located in the leading edge of the sprouting vessel. Tip cell then induces stalk cells characterized by non-motile, proliferative, tubulogenic cells. So far, Notch receptor signaling, activated by Dll4 in tip cells, is the key regulator for inducing stalk cells. However, the molecule that is responsible for these active properties of tip cell and how Dll4/Notch signaling inhibits this molecule in stalk cell is still not clear. And also, there have been only few studies about transcription factor regulating tip/stalk formation. Here, we show the role of transcription factor Sox17 in tip/stalk cell specification and sprouting angiogenesis. In the developmental vessel, Sox17 was highly expressed in most of the endothelial cell and not in the mural cell. Loss of Sox17(Sox17 LOF) in endothelial cell using Tie2-cre;Sox17gfp/fl embryo resulted in vascular remodeling defect and subsequent arrest in the primitive capillary plexus stage. Gain of endothelial Sox17(Sox17 GOF) using VE-cadherin tTA;TetO-Sox17 mice resulted in increased vascular density, sprouting, filopodial extrusion throughout the developmental period. This excessive vascular remodelling in Sox17 GOF mutant also resulted in disruption of vascular integrity, loss of endothelial cell polarity, lack of vascular lumen formation and missing of circulating hematopoietic cells. In the adult stage, Sox17 expression was restricted to arteries in quiescent vessels. However in angiogenic condition like tumor, Sox17 was re-elevated in endothelial cells. Sox17 LOF model LLC tumor showed reduced vascular density and reduced filopo...