**3. Pulmonary vascular remodelling**

striction (HPV). However, neither the oxygen sensing process nor the exact HPV pathways are fully understood [21]. The effector pathway is suggested to include L-type calcium channels, non-specific cation channels and voltage-dependent potassium channels, whereas mitochondria and nicotinamide adenine dinucleotide phosphate oxidases have been described as oxygen sensors (Figure 1). Reactive oxygen species (ROS), redox couples and adenosine monophosphate-activated kinases are also under investigation as mediators of HPV. More‐ over, the role of calcium sensitisation, intracellular calcium stores and direction of change of reactive oxygen species is still under debate. Other pathways, such as the endothelin-1 pathway, nitric oxide pathway and ROS may also explain development of sustained PH. Endothelin-1 is an important mediator of systemic hypertension in intermittent hypoxic states [18,22] and ongoing studies suggest a role for endothelin in acute HPV. ROS are highly reactive and unstable free radicals. Intermittent hypoxia stimulates the synthesis and release of ROS through the tyrosine hydroxylase system, leading to the development of systemic hyperten‐ sion. ROS have also been implicated in the induction of endothelin-1 and in angiotensinogen synthesis with all these agents believed to contribute to the development of PH induced by

**Figure 1.** Pathways involved in hypoxic pulmonary vasoconstriction. Acute hypoxia results in an increase of intracellu‐ lar calcium in pulmonary arterial smooth muscle cells and thus contraction. This increase in calcium is achieved by in‐ flow of extracellular calcium through plasmalemnal calcium channels and release of intracellularly stored calcium. Hypoxic effects could be mediated or modulated by a decrease (left side) or increase (right side) of reactive oxygen species (ROS). NADPH: reduced nicotinamide adenine dinucleotide phosphate; NSCC: nonspecific cation channels; TRP: transient receptor potential; NADH: reduced nicotinamide adenine dinucleotide; NAD: nicotinamide adenine di‐ nulceotide; NADP: nicotinamide adenine dinucleotide phosphate; CCE: capacitative calcium entry; ATP: adenosine tri‐ phosphate; IP3: inositol triphosphate; cADPR: cyclic ADP-ribose; SR: sarcoplasmatic reticulum; *Sommer N et al. Eur*

*Respir J 2008 [21], Reproduced with permission of the European Respiratory Society*

intermittent hypoxia [18,21,23].

24 Pulmonary Hypertension

Studies of the vasculature in hypoxic PH have demonstrated changes including intimal thickening, medial hypertrophy and muscularization of the small arterioles [5]. When the balance between apoptosis and proliferation of endothelial cells in the pre-capillary pulmonary blood vessels, in particular, is altered in favour of proliferation, the overall resistance pattern is increased [24]. As shown in neonatal calves and rodent models, chronic hypoxia triggers endothelial cell proliferation [24,25]. Acute hypoxia triggers adventitial fibroblast proliferation within hours of exposure while medial hypertrophy and hyperplasia takes longer to develop [24,26,27]. Fibroblasts stimulated by chronic hypoxia can transform into smooth muscle cells. Hyperplasia is more prevalent in the less muscular arterioles, while hypertrophy is more common in the muscular arterioles. Chronic hypoxia in rat models results in a doubling of muscular arteries with proliferation into non-muscularized vessels [24]. The response of pulmonary vascular smooth muscle cells to acute hypoxia is still debatable with some studies indicating reduction in proliferation [24,28].
