Published online before print September 7, 2004, doi: 10.1161/01.CIR.0000141576.39579.23
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(Circulation. 2004;110:1499-1506.)
© 2004 American Heart Association, Inc.
Original Articles |
Disruption of Endothelial-Cell Caveolin-1
/Raft Scaffolding During Development of Monocrotaline-Induced Pulmonary Hypertension
From the Departments of Pediatrics (R.M., J.H., M.G.), Cell Biology & Anatomy (M.S., K.P., P.B.S.), and Medicine (P.B.S.), New York Medical College, Valhalla, NY.
Correspondence to Pravin B. Sehgal, MD, PhD, Basic Sciences Bldg, Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595. E-mail pravin_sehgal{at}nymc.edu
Received February 13, 2004; de novo received April 13, 2004; revision received May 24, 2004; accepted May 25, 2004.
Background— In the monocrotaline (MCT)-treated rat, there is marked stimulation of DNA synthesis and megalocytosis of pulmonary arterial endothelial cells (PAECs) within 3 to 4 days, followed by pulmonary hypertension (PH) 10 to 14 days later. Growing evidence implicates caveolin-1 (cav-1) in plasma membrane rafts as a negative regulator of promitogenic signaling. We have investigated the integrity and function of endothelial cell–selective cav-1
/raft signaling in MCT-induced PH.
Methods and Results— Although PH and right ventricular hypertrophy developed by 2 weeks after MCT, a reduction in cav-1 levels in the lung was apparent within 48 hours, declining to 
30% by 2 weeks, accompanied by an increase in activation of the promitogenic transcription factor STAT3 (PY-STAT3). Immunofluorescence studies showed a selective loss of cav-1 and platelet endothelial cell adhesion molecule-1 in the PAEC layer within 48 hours after MCT but an increase in PY-STAT3. PAECs with cav-1 loss displayed high PY-STAT3 and nuclear immunostaining for proliferating cell nuclear antigen (PCNA). Biochemical studies showed a loss of cav-1 from the detergent-resistant lipid raft fraction concomitant with hyperactivation of STAT3. Moreover, cultured PAECs treated with MCT-pyrrole for 48 hours developed megalocytosis associated with hypo-oligomerization and reduction of cav-1, hyperactivation of STAT3 and ERK1/2 signaling, and stimulation of DNA synthesis.
Conclusions— MCT-induced disruption of cav-1 chaperone and scaffolding function in PAECs likely accounts for diverse alterations in endothelial cell signaling in this model of PH.
Key Words: endothelium • hypertension, pulmonary • interleukins • signal transduction • transcription factors
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