Hypoxia-induced vascular remodelling.
The initial structural changes include endothelial blebbing and disruption of the endothelial barrier, allowing influx of plasma proteins, including growth factors. The hallmark of remodelling is the extension of vascular smooth muscle to previously unmuscularised arterioles. Medial and adventitial thickening are also observed, the former from smooth muscle cell hypertrophy as well as accumulation of smooth muscle cells, the latter from an increase in fibroblasts and myofibroblasts and in extracellular matrix. An influx of inflammatory cells is also evident but less pronounced than in, for example, pulmonary arterial hypertension (PAH).
Indeed, the remodelling witnessed with hypoxia differs from that seen with PAH in that with most species, including man, it is less severe than in PAH and there is no occlusion of vessels; one exception is the neonatal hypoxic calf model which can develop marked intimal thickening associated with a very high PAP (Stenmark et al., 1987). Moreover, the concept that hypoxia leads to an increase in PVR from remodelling that narrows the vessel lumen has been challenged, as has the idea that hypoxia leads to vascular rarefaction or “pruning”. Hypoxia stimulates angiogenesis. Studies in rats have reported that chronic hypoxia increases total pulmonary vessel length, volume, endothelial surface area and the number of endothelial cells. Coupled with experimental studies in rodents that show that inhibition of the anti-angiogenic factor, angiostatin, aggravates and that overexpression of vascular endothelial growth factor protects rats from hypoxia-induced pulmonary hypertension, the suggestion is that, at least in rodents, angiogenesis plays a significant role in the response of the pulmonary circulation to chronic hypoxia, perhaps acting to reduce the effects of HPV and structural changes elsewhere on the right ventricle.
An increase in haemodynamic stress with hypoxia is a factor in initiating and perhaps sustaining pulmonary vascular remodelling; banding of the pulmonary artery has been shown to prevent and reverse occlusive lesions in a hypoxia-dependent rodent model of pulmonary hypertension (Abe et al., 2016). Unlike the immediate vasoconstrictor response to hypoxia, vascular remodelling requires new protein synthesis. A panoply of factors (reviewed elsewhere)(Wilkins, Ghofrani, Weissmann, Aldashev & Zhao, 2015) have been implicated in mediating the structural changes, from vasoactive molecules (such as endothelin) to growth factors (e.g. platelet-derived growth factor) and cytokines (e.g. interlukine-6 and tumour necrosis factor-α). Changes in the underlying response of vascular cells to these factors are also involved. Not surprisingly, the role of hypoxia-inducible factors (HIFs) and their target genes are of primary interest.