Crosstalk between oxygen- and nitric oxide-dependent signaling pathways in angiogenesis

With every heart beat blood rushes through a complex network of tubes to deliver essential ingredients of life, oxygen and nutrients. Consequently, this network of blood vessels is an indispensable part of vertebrate physiology. Its organization and architecture is highly dynamic in its form and function. Understanding how blood vessels develop, a process referred to as angiogenesis, is equally important as to know how they function considering that failure or misalignment of this process results in disorder and disease, in many cases of which death is inevitable. Much has been learned about the angiogenic process and the critical contributors of blood vessel function. A central determinant is oxygen, an evident contributor given the fact that oxygen delivery is a primary feature of blood vessel function. Not only is oxygen however essential for mitochondrial energy production, it also serves as a key molecule in various biochemical reactions, such as the formation of nitric oxide (NO), on its part a critical regulator of vascular tone and vessel homeostasis. Hence, oxygen abundance relates to the production of NO, and NO in turn regulates oxygen delivery and consumption. Given the importance of the intrinsic link these two molecules exert on angiogenesis and vessel function; this review shall highlight our current understanding on how these two molecules cooperate to form blood vessels.

► Oxygen abundance steers the angiogenic process via the oxygen sensing system.
► Endothelial and macrophage O2 sensors exert different roles in angiogenesis and arteriogenesis.
► Nitric oxide (NO) and oxygen abundance converge to regulate angio- and arteriogenesis.
► HIF-1α stimulates NO production by induction of iNOS steering angiogenesis.
► HIF-2α antagonizes NO production and angiogenesis by stimulating arginase expression.