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(Circulation Research. 2004;94:1001.)
© 2004 American Heart Association, Inc.

Editorials

The Mouse Through the Looking Glass

A New Door Into the Pathophysiology of Pulmonary Hypertension

Marlene Rabinovitch

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 marlener@stanford.edu

See related article, pages 1109–1114

Key Words: pulmonary hypertension • bone morphogenetic protein receptor • smooth muscle cells • transgenic mouse • hypoxia

An extract of the first 250 words of the full text is provided, because this article has no abstract.

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-ß (TGF-ß) or BMP-2.¹² In other studies, pulmonary artery smooth muscle cells were transfected with constructs encoding different mutant forms of BMP-RII expressing . . . [Full Text of this Article]

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