Exploiting porphyrin metabolism to inhibit angiogenesis

Heme is an essential iron-containing porphyrin that plays a critical role in endothelial cell (EC) function, regulating processes such as cell signalling and energetic metabolism. Nevertheless, the role of de novo heme synthesis and porphyrin metabolism during angiogenesis remains poorly understood. In this study, a pharmacological approach using 5-aminolevulinic acid (ALA) was employed to dysregulate heme/porphyrins homeostasis in EC. ALA treatment resulted in intracellular porphyrins accumulation and extensive release into the extracellular environment. ALA-treated EC exhibited diminished proliferation and migration, as well as reduced ability to form tubule-like structures, which led to impaired ex vivo angiogenic sprouting and in vivo angiogenesis in the developing retina. Moreover, ALA inhibited pathological neovascularization in the oxygen-induced retinopathy mouse model that recapitulates the vascular alterations occurring in human patients affected by retinopathy of prematurity and diabetic retinopathy. Importantly, extracellular porphyrins contributed to the observed anti-angiogenic effects. These findings underscore the biological impact of endogenous porphyrins on EC function and angiogenesis, providing insights into potential therapeutic applications for human diseases characterized by aberrant vascularization, including neovascular eye diseases.