Deciphering the "matrix" in pulmonary vascular remodelling

Abstract

Vascular remodelling, a prominent feature of pulmonary arterial hypertension (PAH), is characterised by changes affecting all layers of the pulmonary vessels. The intima becomes infiltrated with fibroblasts and shows prominent fibrosis. The media is the site of smooth muscle hypertrophy and extension of muscle to normally nonmuscularised peripheral arteries as a result of differentiation of pericytes and/or recruitment of smooth muscle cell (SMC) precursors. Similarly, there is increased production of extracellular matrix (ECM), with deposition of collagen and elastin, contributing to the remodelling of the adventitia. The factors that initiate and/or participate in ECM remodelling have been the focus of investigations mostly in animal models of pulmonary hypertension 1. It has been postulated that matrix remodelling may be preceded by endothelial dysfunction, with alterations in barrier properties leading to the accumulation of a serum factor in the subendothelial space 2. This putative factor would, in turn, cause activation of a SMC serine elastase 3. Several lines of evidence obtained from animal experimentation and human studies support the concept that increased elastolytic activity contributes to the pathogenesis of pulmonary hypertension through remodelling of the ECM. Indeed, elastin fragmentation has been observed in the pulmonary arteries of children afflicted with pulmonary hypertension related to congenital heart defects 4. In addition, while high elastin turnover in conjunction with increased activity of a serine elastase has been observed at least in monocrotaline-induced …