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Pharmacol Ther. 2001 Oct;92(1):1-20.

Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension.

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  • 1Department of PhysiologyPharmacology, The University of Queensland, St Lucia, Brisbane, Queensland, 4072, Australia.

Abstract

Pulmonary vascular remodelling is an important pathological feature of pulmonary hypertension, leading to increased pulmonary vascular resistance and reduced compliance. It involves thickening of all three layers of the blood vessel wall (due to hypertrophy and/or hyperplasia of the predominant cell type within each layer), as well as extracellular matrix deposition. Neomuscularisation of non-muscular arteries and formation of plexiform and neointimal lesions also occur. Stimuli responsible for remodelling involve transmural pressure, stretch, shear stress, hypoxia, various mediators [angiotensin II, endothelin (ET)-1, 5-hydroxytryptamine, growth factors, and inflammatory cytokines], increased serine elastase activity, and tenascin-C. In addition, there are reductions in the endothelium-derived antimitogenic substances, nitric oxide, and prostacyclin. Intracellular signalling mechanisms involved in pulmonary vascular remodelling include elevations in intracellular Ca2+ and activation of the phosphatidylinositol pathway, protein kinase C, and mitogen-activated protein kinase. In animal models of pulmonary hypertension, various drugs have been shown to attenuate pulmonary vascular remodelling. These include angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, ET receptor antagonists, ET-converting enzyme inhibitors, nitric oxide, phosphodiesterase 5 inhibitors, prostacyclin, Ca2+ -channel antagonists, heparin, and serine elastase inhibitors. Inhibition of remodelling is generally accompanied by reductions in pulmonary artery pressure. The efficacy of some of the drugs varies, depending on the animal model of the disease. In view of the complexity of the remodelling process and the diverse aetiology of pulmonary hypertension in humans, it is to be anticipated that successful anti-remodelling therapy in the clinic will require a range of different drug options.

PMID:
11750034
[PubMed - indexed for MEDLINE]
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