FIGURE 5.

Hypothesis of hypoxia-inducible factor-2 (HIF-2) as a “switch” between the vascular and nonvascular phenotypes in COPD. HIF-2 might represent a molecular “switch” between progression into a vascular or nonvascular phenotype. Under the influence of multiple exogenous and endogenous factors, maladaptive upregulation of HIF-2 in endothelial cells, alveolar type 2 cells and some types of bronchial cells may result in predominant vascular involvement, with pronounced remodelling and severe (out-of-proportion) pulmonary hypertension, but relatively preserved airways and alveolar-capillary units of the lung (the vascular phenotype). Loss of adaptive HIF-2 upregulation (HIF-2 downregulation) in the mentioned cells leads to the loss of alveoli and/or small bronchioles, but mild-to-moderate vascular remodelling and proportionate pulmonary hypertension.