HMOX1 and diabetes mellitus: The profound effects of hypoxia on ECM homeostasis are displayed in various pathological conditions, such as diabetes and tumorigenesis.25,26 Collagen lysyl hydroxylase 2 (PLOD2), an essential collagen-modifying enzyme12,27,28 that affects cross-linking by LOX family enzymes of type I and III collagens (the primary collagens at HO sites),29,30 is induced upon exposure to hypoxia in a HIF-1α, not HIF-2α, dependent manner.