The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis?

Abstract

Chronic lung disease in humans is frequently complicated by the development of secondary pulmonary hypertension, which is associated with increased morbidity and mortality. Hypoxia, inflammation and increased shear stress are the primary stimuli although the exact pathways through which these initiating events lead to pulmonary hypertension remain to be completely elucidated. The increase in pulmonary vascular resistance is attributed, in part, to remodelling of the walls of resistance vessels. This consists of intimal, medial and adventitial hypertrophy, which can lead to encroachment into and reduction of the vascular lumen. In addition, it has been reported that there is a reduction in the number of blood vessels in the hypertensive lung, which could also contribute to increased vascular resistance. The pulmonary endothelium plays a key role in mediating and modulating these changes. These structural alterations in the pulmonary vasculature contrast sharply with the responses of the systemic vasculature to the same stimuli. In systemic organs, both hypoxia and inflammation cause angiogenesis.Furthermore, remodelling of the walls of resistance vessels is not observed in these conditions. Thus it has been generally stated that, in the adult pulmonary circulation, angiogenesis does not occur. Prompted by previous observations that chronic airway inflammation can lead to pulmonary vascular remodelling without hypertension, we have recently shown, using quantitative stereological techniques, that angiogenesis can occur in the adult pulmonary circulation. Pulmonary angiogenesis has also been reported in some other conditions including postpneumonectomy lung growth, metastatic disease of the lung and in biliary cirrhosis. Such angiogenesis may serve to prevent or attenuate increased vascular resistance in lung disease. In view of these more recent data, the role of structural alterations in the pulmonary vasculature in the development of pulmonary hypertension should be carefully reconsidered.

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

“…Moreover, cor pulmonale is an independent predictor of increased mortality, suggesting that pulmonary hypertension contributes directly to reduced survival (1,2). The increased pulmonary vascular resistance underlying chronic hypoxic pulmonary hypertension is accompanied by characteristic changes in the blood vessels, which include remodeling and thickening of the walls of precapillary vessels and sustained vasoconstriction (3)(4)(5)(6)(7)(8).…”

Endothelial progenitors in pulmonary hypertension: new pathophysiology and therapeutic implications: Fig. 1—

“…In the middle between these two opposite forms of PH, there are lung diseases in which angiogenesis and vascular rarefaction occur at the same time [49]. For instance, bronchial asthma shares some features of pulmonary emphysema but is associated with bronchial submucosal neo-angiogenesis [51], while acute lung injury and adult respiratory distress syndrome display features of both capillary involution and neo-angiogenesis.…”

“…This scenario is best represented by the patient with emphysema, in whom chronic hypoxia and loss of septum-associated capillaries lead to PH, which manifests or worsens during exercise. The most obvious mechanism for development of this form of PH appears to be vascular rarefaction, while expansion of the capillary bed through neo-angiogenesis would be intuitively desirable in this setting to restore the pulmonary microvascular bed and lower pulmonary pressures [49].…”

Role of Notch Signaling in Pulmonary Hypertension

“…In previously muscularized vessels, medial thickening is caused by hypertrophy and hyperplasia of the existing smooth muscle cells (SMCs) [19]. Increased proliferation of the cells is accompanied with a decreased rate of apoptosis.…”

“…In pre--capillary (non--muscularized) vessels, de novo formation of muscular media is observed. Smooth muscle cells, which form the new media, are suggested to be derived from either differentiation of intermediate cells present in the vessels or from migration and differentiation of adventitial fibroblasts [19,20].…”