What causes Pulmonary Arterial Hypertension?

The exact cause of Pulmonary arterial hypertension (PAH) remains unknown. However, continuous research into the disease has led to a better understanding of the processes involved.

The first stage involves changes to particular types of cells that line the lungs and arteries, called endothelial cells.  In recent years research has focused particularly on the role of three specific substances that are produced in these cells: Prostacyclin, nitric oxide and endothelin. These three agents work together to help the blood to flow smoothly through the heart and lungs and it is thought that an imbalance in levels of one or more of these substances contributes to the development of conditions such as Pulmonary Arterial Hypertension (PAH). This leads to the progressive changes in the vessels and the subsequent rise in pressure. This area of research has led to the development of specific treatments for Pulmonary Arterial Hypertension (PAH). Click here for further information about treatment of Pulmonary Arterial Hypertension (PAH) 

Prostacyclin

Prostacyclin is produced by the Endothelium, a cell layer lining the blood vessels. It causes the blood vessels to relax (is known as 'vasodilator'), allowing the blood to flow more easily, and it also prevents cells from multiplying excessively.

Patients with Pulmonary Arterial Hypertension (PAH) typically have low levels of prostacyclin and this is thought to be one of the factors thought to contribute to the blood vessels in the lungs becoming constricted.¹ Prostaglandin therapy with synthetic forms of prostacyclin can help to correct this deficiency, although administering this form of treatment can be complex.^2,3

Nitric oxide

Nitric oxide, like prostacyclin, allows the blood vessels to relax and helps to prevent the number of cells from multiplying excessively. People with Pulmonary Arterial Hypertension (PAH) often produce insufficient nitric oxide and this can contribute to the development of the disease.¹

Endothelin

Endothelin is produced by the endothelium and is essential for a number of functions, including the regulation of normal blood flow. However, it has been shown that people with Pulmonary Arterial Hypertension (PAH) produce too much endothelin. ^4,5,6  Excessive levels of endothelin can have a number of detrimental effects in the body including:

• thickening and scarring of tissue and blood vessels (Fibrosis)

• enlargement or increase in the number of cells in the vessel wall, which can lead to thickening and obstruction of the blood vessels

• Inflammation

• narrowing of the blood vessels (Vasoconstriction)

Once it is released from the endothelium, endothelin binds to specific receptors in a similar way to a key fitting into a lock. There are two types of Endothelin receptors, ET_A and ET_B, and each type has a slightly different action.⁷  A class of drugs, endothelin receptor antagonists (ERAs) aim to reduce the impact of PAH by helping to protect against the damaging effects of excessive endothelin.

References
1.  MacGreggor AJ, Canavan R, Knight C et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001;40(4):453-9
2. Galie N, Manes A, Branzi A. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiov Dis 2003:45: 213-24
3. Clapp LH, Finney P, Turcato S et al. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human Pulmonary artery. Am J Resp Cell Mol Biol 2002;2: 194-201
4. Stewart DJ, Levy RD, Cernacek P et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Inter Med 1991; 114:464-9.
5. Vancheeswaran R, Magoulas T, Efrat G et al. Circulating endothelin-1 levels in systemic sclerosis subsets--a marker of fibrosis or vascular dysfunction? J Rheum 1994; 21:1838-44
6. Yoshibayashi M, Nishioka K, Nakao K et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation 1991; 84:2280-5
7. Levin ER, Epstein FH (ed). Mechanisms of diseases: endothelins. N Engl J Med 1995;333: 356-63