Caveolin-1 expression during the progression of pulmonary hypertension.
Caveolin-1 plays a pivotal role in maintaining vascular health. Progressive loss of endothelial caveolin-1 and activation of proliferative and anti-apoptotic pathways occur before the onset of monocrotaline (MCT)-induced pulmonary hypertension (PH), and the rescue of endothelial caveolin-1 attenuates PH. Recently, we reported endothelial caveolin-1 loss associated with enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation in human PH. To examine whether the loss of endothelial caveolin-1 followed by an enhanced expression in SMC is a sequential event in the progression of PH, we studied rats at two and four weeks post-MCT. Right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary vascular histology, and the expression of caveolin-1 and endothelial membrane proteins (platelet/endothelial cell adhesion molecule-1 [PECAM-1], both α and β subunits of soluble guanylate cyclase [sGC]), von Willebrand factor (vWF), smooth muscle α-actin, proliferative and anti-apoptotic factors (PY-STAT3 and Bcl-xL) and matrix metalloproteinase (MMP) 2 in the lungs were examined. PH was accompanied by a progressive loss of endothelial caveolin-1, activation of PY-STAT3, increased Bcl-xL expression and vascular remodeling at two and four weeks post-MCT. Loss of PECAM-1 and sGC (both subunits) paralleled that of caveolin-1, whereas vWF was well preserved at two weeks post-MCT. At four weeks post-MCT, 29% of the arteries showed a loss of vWF in addition to endothelial caveolin-1, and 70% of these arteries exhibited enhanced expression of caveolin-1 in SMC; and there was increased expression and activity of MMP2. In conclusion, MCT-induced endothelial injury disrupts endothelial cell membrane with a progressive loss of endothelial caveolin-1, and the activation of proliferative and antiapoptotic pathways leading to PH. Subsequent extensive endothelial cell damage results in enhanced expression of caveolin-1 in SMC. In addition, there is a progressive increase in MMP2 expression and activity. These alterations may further facilitate cell proliferation, matrix degradation and cell migration, thus contributing to the progression of the disease.
Section of Pediatric Cardiology, Maria Fareri Children's Hospital, New York Medical College, Valhalla, NY 10595, USA.
Jing
J
Huang
John H
JH
Wolk
Michael H
MH
Gewitz
Rajamma
R
Mathew
D000818:Animals; D051242:Caveolin 1 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008168:Lung / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D016686:Monocrotaline / Q000008:administration & dosage; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D051242:Caveolin 1; D016686:Monocrotaline; D020778:Matrix Metalloproteinase 2