Reversal of experimental pulmonary hypertension by PDGF inhibition
Ralph Theo Schermuly, … , Werner Seeger, Friedrich Grimminger
Ralph Theo Schermuly, … , Werner Seeger, Friedrich Grimminger
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2811-2821. https://doi.org/10.1172/JCI24838.
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Research Article Vascular biology Article has an altmetric score of 18

Reversal of experimental pulmonary hypertension by PDGF inhibition

Abstract

Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antiremodeling therapy in progressed pulmonary hypertension.

Authors

Ralph Theo Schermuly, Eva Dony, Hossein Ardeschir Ghofrani, Soni Pullamsetti, Rajkumar Savai, Markus Roth, Akylbek Sydykov, Ying Ju Lai, Norbert Weissmann, Werner Seeger, Friedrich Grimminger

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Effects of STI571 on the degree of muscularization; medial wall thicknes...
Effects of STI571 on the degree of muscularization; medial wall thickness of pulmonary arteries sized 25–50 μm, 51–100 μm, and greater than 100 μm; and internal lumen area of pulmonary arteries sized 25–50 μm. (A) Proportion of non- (N), partially (P), or fully (M) muscularized pulmonary arteries, as percentage of total pulmonary artery cross section (sized 25–50 μm). A total of 60–80 intraacinar vessels was analyzed in each lung. (B–D) Medial wall thickness of pulmonary arteries sized 25–50 μm (B); 51–100 μm (C); and greater than 100 μm (D). (E) The internal lumen area of vessels between 25 and 50 μm. Results from rats exposed to MCT for 28 and 42 days and STI571-treated rats (treatment from day 28 to 42 with 50 mg/kg/d) are presented. (F) Proportion of non-, partially, or fully muscularized pulmonary arteries from chronically hypoxic mice treated with STI571 (sized 20–70 μm). STI571 was applied at a dose of 100 mg/kg/d by gavage from day 21 to 35. *P < 0.05 versus control; †P < 0.05 versus MCT at day 28 or hypoxia at day 21; ‡P < 0.05 versus MCT at day 42 or hypoxia at day 35.