Fig. 1.

Adaptation of endothelial cells to inflammatory stimuli and hypoxia. Upper part, the classical (canonical) NFκB pathway is activated by various mediators and their receptors and involves liberation of the NFκB (p65/p50) after phosphorylation and degradation of IκBα, -β, and -ε (indicated as IκBα). In addition, lymphotoxin and CD40 ligand can further influence endothelial activation probably via the non-canonical NFκB pathway or part of it. Further details are given in the text. Lower part, left, the two prolines of the α-subunits of HIF-1 and HIF-2 are hydroxylated by proline hydoxylase-2 (PHD-2), which requires oxygen (O ₂), after which they bind do von Hippel–Lindau (VHL) protein and are degraded in the proteasome. The lack of oxygen (lower part, right) causes rescue of the α-subunits of HIF-1 and HIF-2, which—after nuclear entry—each dimerize with HIF1β and activate numerous genes. The endothelial response varies with that of many other cells as both HIF1 and HIF2 become active, while most tissue cells express only HIF1 subunits. Hypoxia can also induce unfolded protein stress, which via activation of IRE1 and subsequent steps can activate IKK and subsequently NFκB. Abbreviations: NOX NADPH oxidase; other abbreviations are given in the text