Associate editor: R.M. Wadsworth
Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension

https://doi.org/10.1016/S0163-7258(01)00157-7Get rights and content

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.

Introduction

Pulmonary hypertension is characterised by elevations in pulmonary artery pressure and pulmonary vascular resistance. There are multiple aetiologies of pulmonary hypertension (some of which are listed in Table 1) and also a variety of animal models of the disease (Table 2). However, the two pathological features that are common to most, if not all, forms of pulmonary hypertension are abnormal pulmonary vasoconstriction and alterations in pulmonary vascular structure (pulmonary vascular remodelling); both of these features contribute to the elevations in pressure and resistance. Drugs in current use for the treatment of pulmonary hypertension are mainly vasodilators, including Ca2+-channel antagonists, prostacyclin (prostaglandin I2), and nitric oxide (NO) gas (for a review, see Wanstall & Jeffery, 1998). As vasodilators, each of these drug types acts by opposing any abnormal vasoconstriction. Since abnormal vasoconstriction becomes progressively less important and vascular remodelling progressively more important as the disease advances (Reeves et al., 1986), an alternative, and possibly more fruitful, approach may be to target pulmonary vascular remodelling.

Section snippets

Characteristics of pulmonary vascular remodelling

Pulmonary vascular remodelling is characterised by thickening of all three layers of the blood vessel wall, viz., the adventitia, the media, and the intima. The thickening is due to hypertrophy (cell growth) and/or hyperplasia (proliferation) of the predominant cell type within each of the layers (i.e., fibroblasts, smooth muscle cells, and endothelial cells), as well as increased deposition of extracellular matrix components (e.g., collagen, elastin, and fibronectin). Thickening of the media

Methods used to assess pulmonary vascular remodelling

A variety of methods have been used to assess the different aspects of pulmonary vascular remodelling. Medial thickening of pulmonary arteries and neomuscularisation of normally non-muscular arteries can be assessed histologically in lung sections stained for smooth muscle (e.g., van Gieson’s stain) and elastin (e.g., Miller’s stain or Verhoeff’s stain), or immunolabelled with antibodies for smooth muscle α-actin. The conditions under which the lungs are fixed vary between laboratories. The

Mechanisms of pulmonary vascular remodelling

Pulmonary vascular remodelling occurs in response to a wide variety of stimuli, both physical (e.g., mechanical stretch, shear stress) and chemical (e.g., hypoxia, vasoactive substances, growth factors). Moreover, within any population of pulmonary vascular cells there is heterogeneity in their response, not only to the various growth promoting and proliferative stimuli, but also to mediators that inhibit growth Wohrley et al., 1995, Dempsey et al., 1997, Frid et al., 1997, Wharton et al., 2000

Consequences of pulmonary vascular remodelling

There are several physiological consequences of pulmonary vascular remodelling. First, the increase in smooth muscle in the media of muscular arteries, and also neomuscularisation of distal arteries, results in exaggerated increases in wall tension in response to contractile stimuli (i.e., vasoconstrictor agents, hypoxia). This is a nonspecific effect that simply reflects the increased amount of smooth muscle in the vessel wall, and is independent of any specific changes in sensitivity to

Therapeutic interventions for the inhibition of pulmonary vascular remodelling

There are various animal studies in which different drug types have been investigated for their effects on pulmonary vascular remodelling in pulmonary hypertension. Some of these drug types have also been used in clinical trials. From the clinical trials, information on pulmonary artery pressure and/or survival is available, but data specifically on pulmonary vascular remodelling are lacking. One exception to this generalisation is the study of Wilkinson et al. (1988) in which pulmonary

Conclusion

Pulmonary vascular remodelling in pulmonary hypertension is a complex, multi-factorial process, with many of the physical and chemical stimuli for remodelling acting synergistically and/or interdependently (Fig. 3). In view of the complexity of remodelling, drug therapy that targets more than one aspect of the process is likely to be more effective than any drug that interferes at only one point in the cascade of events. This could be achieved with drugs possessing more than one action (e.g., a

Acknowledgements

The financial support of the National Health and Medical Research Council of Australia is gratefully acknowledged.

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