The exact causes behind the development of PAH remain unknown. However, research has led to a better understanding of the underlying pathological mechanisms.

PAH is recognised as a complex, multifactorial condition involving numerous biochemical pathways and different cell types.1,2

Endothelial dysfunction, an abnormality of the inner lining of blood vessels, is believed to occur early in disease pathogenesis. This leads to endothelial and smooth muscle cell proliferation followed by structural changes or remodelling of the pulmonary vascular bed, which in turn results in an increase in pulmonary vascular resistance (PVR).3


Vascular remodelling

This involves every layer of the vessel wall and is characterised by proliferative and obstructive changes involving many cell types, including endothelial cells, smooth muscle cells and fibroblasts.1,3 Inflammatory cells and platelets may also play a significant role in PAH.3

Figure 1. Vasoconstriction due to vessel wall remodelling

Endothelial dysfunction results in chronically impaired production of vasoactive mediators, such as nitric oxide and prostacyclin, along with prolonged overexpression of vasoconstrictors, such as endothelin-1 (ET-1), which not only affect vascular tone, but also promote vascular remodelling.1 These substances are important therapeutic targets for treatment options in PAH.4 Click here for information about the treatment of PAH.



The increase in PVR observed in patients with PAH is related to a number of progressive changes in the pulmonary arterioles, including:1

  • Vasoconstriction
  • Obstructive remodelling of the pulmonary blood vessel walls
  • Inflammation
  • In situ thrombosis

Figure 2. Pathological changes in pulmonary arterioles

The most prominent histological feature of PAH is a thickening of the three cellular layers (the intima, media and adventitia) that line the blood vessels, which is due to a process of cell enlargement termed hypertrophy. Other changes include the development of plexiform lesions, a classic characteristic of PAH (proliferations of endothelial and smooth muscle cells at an arterial branch point).5


Increased pulmonary artery pressure puts strain on the heart.

The increase in pulmonary arterial pressure (afterload) makes the right heart work harder, resulting in right ventricular hypertrophy. Initially, the heart is able to compensate for the increased pressure; however, as the disease progresses, the right ventricle (RV) becomes dilated, eventually resulting in RV failure and death.1


  1. Galiè N, et al. Eur Heart J 2009;30:2493–537
  2. McLaughlin VV, et al. Circulation 2009;119:2250–94
  3. Montani D, et al. Orphanet Rare J Dis 2013;8:97
  4. Malenfant S, et al. Expert Rev Respir Med 2013;7(1):43–55
  5. Jonigk D, et al. Am J Pathol 20122;179:167–79

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