More than a ring: the emerging role of heme in angiogenesis.

Heme is an essential iron-containing porphyrin of vital importance for all cells, including endothelial cell (EC). Indeed, due to its involvement in several biological processes, including gene transcription regulation, energy production, anabolic processes, heme metabolism is critically required in high-energy-demanding processes like angiogenesis. Over the past decade, growing evidence has identified heme metabolism as a central regulator of the angiogenic process. Hence, targeting heme synthesis and homeostasis could offer valuable therapeutic opportunities to modulate pathological neovascularization, as in ocular neovascularization diseases and cancer, and, potentially, to support neo-vascular growth in conditions characterized by insufficient blood supply as ischemia and stroke.The present review summarizes the literature on heme and angiogenesis, emphasizing the novel functions of heme, beyond its more canonical role as cofactor in hemoproteins and addressing how heme homeostasis can orchestrate a plethora of endothelial functions indispensable for angiogenesis.