The mouse through the looking glass: a new door into the pathophysiology of pulmonary hypertension.

Idiopathic pulmonary artery hypertension (IPH) is a rare illness with a poor prognosis. Whereas chronic intravenous prostacyclin relieves some of the symptoms of progressive dyspnea and prolongs survival, most patients ultimately require a lung transplant.1 Newer therapies such as nonintravenously administered prostacyclin derivatives,2,3,4 endothelin receptor blockers,5,6 and, to some extent, phosphodiesterase inhibitors,7 hold some promise as alternatives for intravenous prostacyclin, but current expectation is that, like prostacyclin, they will, at best, retard disease progression, serving as a bridge to transplant rather than as an alternative. The pathological features of IPH are loss of small distal precapillary pulmonary arteries, obliterative changes (plexogenic lesions) in more proximal pulmonary arteries associated with migration and proliferation of smooth muscle cells, and increased extracellular matrix deposition. There is also dysregulation of endothelial cells associated with increased proliferation.8 The mechanism underlying the evolution of these changes is unknown, so there was great interest when 2 groups independently identified a mutation in bone morphogenetic protein receptor 11 (BMP-RII) in 60% of families with IPH.9,10 A BMP-RII mutation also occurs in 20% of sporadic cases of IPH,11 but the biological connection between the mutation and the pathobiology of IPH has been relatively elusive. Recent studies using pulmonary artery smooth muscle cells from patients with IPH, including those with and without a BMP-RII mutation, showed similar abnormal proliferation in response to agents such as transforming growth factor(TGF) or BMP-2.12 In other studies, pulmonary artery smooth muscle cells were transfected with constructs encoding different mutant forms of BMPRII expressing aberrant kinase or cytoplasmic domains, and impaired signaling was observed related to alterations in the induction of Smads and p38.13 Specifically, suppression of Smad1/5 and activation of p38 were related to smooth muscle cell proliferation. It is still unknown specifically how these abnormalities in signaling regulate genes that induce smooth muscle cell proliferation or the more complex features associated with obliterative vascular lesions and plexiform changes that are related to aberrant endothelial function, smooth muscle cell migration and abnormal matrix production,14 or sensitivity or resistance to apoptosis.15,16 One possibility it that there is altered function of a transcription factor that binds Smad proteins, such as AML117 (Figure). This is intriguing because we have related AML1 to the induction of an elastase enzyme18 that is pivotal to the progression of pulmonary hypertension in animal models.19 Quite recently, using a yeast 2-hybrid system, mutations in the cytoplasmic tail of BMP-RII have been linked to altered interaction with a microtubule-associated protein, but the significance of this abnormality remains to be determined.20 It would therefore be valuable to create a mouse in which the vascular pathology related to the mutation could be evaluated. Deletion of BMP-RII in the mouse is lethal in embryonic life,21 and the heterozygote has a relatively unremarkable phenotype. So it is with great interest that we read in this issue of Circulation Research a report from the laboratory of Dr David Rodman22 describing the development of pulmonary hypertension in a mouse induced by overexpressing the human BMP-RII mutation in vascular smooth muscle cells in the postnatal period. This is achieved by driving expression of the BMP-RII mutation with the SM22 vascular smooth muscle-specific promoter under the regulation of tetracycline. The mice described have pulmonary hypertension in room air and more severe pulmonary hypertension than control mice in Denver altitude or with hypoxia. This more severe pulmonary hypertension is associated with a relatively modest increase in the number of muscularized distal vessels and in the hypertrophy of the more proximal pulmonary arteries. Although these features do not recapitulate the full pathology found in IPH patients, they are common to all forms of pulmonary hypertension regardless of etiology. Thus, the authors of this report are able, for the first time, to link the mutation to the pathobiology of pulmonary hypertension in an intact animal. With the proviso that the mouse and human respond similarly, the report also suggests that there is a link between the early pulmonary arterial changes common to all patients with pulmonary hypertension and the later obliterative changes in IPH. The progression from increased muscularity of pulmonary arteries to obliterative neointimal formation has been observed in pulmonary hypertension associated with congenital heart defects but has not been shown in IPH, perhaps because the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pediatrics, Stanford University, Calif. Correspondence to Marlene Rabinovitch, MD, Stanford University, Department of Pediatrics, Room 2245B, 269 Campus Drive, Stanford, CA 94305-5168. E-mail [email protected] (Circ Res. 2004;94:1001-1004.) © 2004 American Heart Association, Inc.