Need glucose to sprout: local metabolic control of angiogenesis

Abstract

Much of the focus of research in angiogenesis has been on the molecular mechanisms regulating various critical endothelial cell processes such as migration, proliferation and capillary sprouting. This has led to a number of insights including the key roles played by VEGF signalling in initiating angiogenesis (Chung & Ferrara, 2011; Koch & Claesson‐Welsh, 2012) and Notch signalling in regulating its extent via control of these processes (Benedito & Hellstrom, 2013; Cristofaro et al, 2013; Thomas et al, 2013). This further evolved into therapeutic approaches designed to control angiogenesis by regulation of these signalling events that are now understood in a significant amount of detail. Yet little attention however has been paid so far to the metabolic cost of angiogenesis. All active cellular events, including the ones referred to above, require the expenditure of energy. The underlying assumption has always been that energy ( e.g . ATP) is abundant and is not a limiting factor as endothelial cells are typically found in the high oxygen environment of blood flow. Indeed, while arterial endothelium is bathed in blood with nearly 100 mm Hg of partial pressure of oxygen (PO2), even venous and lymphatic endothelial cells are exposed to a much higher PO2 (∼40 mmHg) than most other tissues. Furthermore, essentially all studies of growth factor signalling in vitro that have given us our current understanding of VEGF and Notch biology, have also been carried out …