Arterial remodelling following pressure overload by aortic constriction: an overlooked and potentially fertile research area

Since first described by Rockman et al., transverse aortic constriction (TAC) has been a model of pressure overload widely used by numerous research groups. Constriction at the aortic arch markedly increases systolic arterial pressure proximal versus distal to the banding site, with diastolic pressure remaining largely unchanged. Thus, the pulse pressure is elevated by twofold to threefold, depending on the degree of constriction. This model shows distinct phases of disease progression, from compensatory hypertrophy to the development of congestive heart failure. The TAC model has proven to be useful in illustrating mechanisms of myocardial hypertrophy and myocardial adaptation, as well as the subsequent factors that contribute to cardiac maladaptation and transition into heart failure. Under conditions of acute and chronic pressure overload, not only the left ventricle (LV), but also the conduit arteries, undergo significant remodelling evoked by the additional hemodynamic stress. The LV and the aorta are serially linked and functionally coupled. The aorta is a characteristically-compliant structure. It expands in systole, which dampens systolic pressure rise and absorbs part of the blood volume ejected into the aorta (Fig. 1). The stored pressure and volume is then released during diastole, thereby maintaining aortic pressure and continuity of forward blood flow. Such a compliant property of the aorta is critical for normal cardiac performance. Thus, loss of the buffering function of a compliant aorta would place extra workload to the LV and concomitantly reduce the coronary artery perfusion pressure (Fig. 1). These changes are particularly harmful in clinical settings of pressure overload, coronary artery disease, and ageing. Large artery remodelling in the TAC model, however, has long been overlooked. In the present issue of Clinical and Experimental Pharmacology and Physiology, Chen et al. studied vascular remodelling in mice subjected to TAC. They found that LV systolic pressure was elevated by 80% at day 3 and 112% by week 2 after TAC. The aortic tree was perfusion fixed, and segments of the aorta proximal and distal to the banding site were separated and analysed using immunohistochemistry and quantitative histology. In animals with TAC, there was no change in the aortic lumen size or the density of vascular smooth muscle cells (VSMC) in the medial layer of the aorta proximal to the banding site. The most notable changes were observed in the adventitial layer of the aorta proximal to the constriction, including thickening of the adventitia and marked increases in the content of collagen and elastin. There was a robust increase in the expression of markers for myofibroblasts, such as a-smooth muscle actin and transgelin, in the adventitia 14 days after TAC, when a thick and fibrotic adventitial layer formed. Another important finding was the accumulation of macrophages in the adventitia 3 days after TAC, which infiltrated into the media and intima at 14 days after TAC. The authors summarized that it is the adventitia in particular that undergoes marked remodelling in the TAC model, and that inflammatory cells might act as a trigger for the changes observed. Large artery remodelling in hypertensive animal models or in patients has been well documented. It usually involves VSMC hypertrophy and hyperplasia of arterial media and increased deposition of extracellular matrix proteins, particularly collagen. Being an interface between circulating blood and vasculature, vascular endothelial cells play an important role in transmitting biomechanical, chemical, and inflammatory signals that regulate the overall growth of VSMC. Blood-born factors (i.e. leukocytes, platelets, and lipids), as well as arterial injury (i.e. endothelial damage, atherosclerosis), would promote hypertrophic remodelling of large arteries. In contrast, changes in the outer layer of the aorta, the adventitia, have received much less attention. The same group of researchers has for many years been working on adventitial remodelling in hypertensive models. They See original article on page 570