Caveolins have emerged as novel signalling molecules acting as signal transducers and mediators of calcium homeostasis. The isoform Cav-1 has been particularly investigated in animal models of pulmonary hypertension and, by one pilot study, in human tissue samples derived from patients with idiopathic pulmonary arterial hypertension [6
Our investigation of the vessel morphometry and the Cav-1 expression in small pulmonary arteries derived from COPD patients with and without concomitant pulmonary hypertension showed a reduction of the Cav-1 expression in the intimal layer of the vessels in patients with pulmonary hypertension. Conversely, the Cav-1 expression in the smooth muscle cell layer was found to be increased in COPD patients with pulmonary hypertension. The ratio of either trend, assessed in a semiquantatitive manner at the light microscopy, was associated with rising pulmonary arterial pressure. Since similar changes were also observed in the expression pattern of an independent smooth muscle cell marker (i.e. α-SMA), it might be suggested that the Cav-1 expression is strongly linked to the vascular distribution of smooth muscle cells.
In pulmonary hypertension, the weak expression of Cav-1 in the intimal layer might be due to an accelerated loss of caveolar peptides through a disrupted and dysfunctional endothelium. Since the bone morphogenetic protein receptor type II (BMPR2), one of the pathogenetic key molecules involved in the development of pulmonary hypertension, co-localizes with caveolins [17
], the loss of Cav-1 might also be explained by the downregulation of the BMPR2 at the endothelial surface of pulmonary arteries as it has been described repeatedly in pulmonary hypertension. The elevated vascular resistance in pulmonary hypertension is mediated by calcium ions that promote the contraction of smooth muscle cells on the molecular level. The weak expression of Cav-1 in the intimal area of pulmonary arteries thus could alternatively be explained by an enhanced transcytosis of calcium by [Ca2+
]-influx channels and ion pumps located on caveolar domains through the endothelium to the smooth muscle cell layer. Conversely, the high expression of Cav-1 observed within the vascular smooth muscle cells in COPD patients with pulmonary hypertension is probably related to increased levels of sarcoplasmic [Ca2+
] due to highly active transient receptor potential channels. It is unclear at the moment, whether the abundant expression of Cav-1 within vascular smooth muscle cells is directly connected to the upregulation of other important signalling molecules in COPD patients with pulmonary hypertension. However, several molecules with pathogenetic relevance for the development of pulmonary hypertension have been located on caveolins including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), receptors for endothelin and serotonine transporters [8
]. Our data thus support the hypothesis that caveolins are involved in the regulation and expression of these factors and, in turn, are of pathogenetic importance for the development of pulmonary hypertension.
The clinical relevance of our findings, on the other hand, is less clear and has to be addressed by further studies. Since novel therapies directed against some of the molecules mentioned above have already been approved for the treatment of pulmonary hypertension, or, at least, are currently under investigation in clinical trials, we believe that caveolins might offer an interesting molecular target for novel therapeutic strategies as well. Along this line, HMG-CoA-reductase inhibitors (statins) were shown to alter the distribution pattern of the cholesterol-enriched caveolins [7
] and their application has been shown to ameliorate pulmonary hypertension in several animal models [24
The “classical” morphological features of pulmonary hypertension such as the formation of a neo-intima and marked hyperproliferation of the smooth muscle cell layer have not been observed in the present study. This might be due to the fact that the increase in pulmonary vascular resistance in COPD-related pulmonary hypertension is generally very moderate. Our study is further limited by the lack of a control group consisting of patients without COPD and the relatively small number of patients. Nevertheless, the findings presented herein are in line with the data from Patel et al, and therefore strongly suggest a common molecular pathway involving caveolar proteins in the development of pulmonary hypertension both in its idiopathic form and in relation with advanced COPD.
In summary, we show for the first time that the expression pattern of Cav-1 within pulmonary arteries is associated with pulmonary hypertension in COPD patients. Consistent with the results from studies performed in tissue samples derived from idiopathic pulmonary arterial hypertension, the expression of Cav-1 was found to be correlated with the pulmonary arterial pressure. Since caveolin has been associated with different molecular players in pulmonary hypertension and, moreover, appears to regulate fibrosis a least in part, our results emphasize a potential novel factor in the pathogenesis of COPD-associated pulmonary hypertension.