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.