Caveolin-1 expression during the progression of pulmonary hypertension

Abstract

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.

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

“…Loss of BMPRII in vivo and in vitro has been shown to increase the production of cytokines such as IL-6, monocyte chemoattractant protein-1, and TGF-␤ (42). It is worth noting here that the reduction in endothelial caveolin-1 associated with increased IL-6 expression and PY-STAT3 occurs in human and experimental forms of PH (11,49,51), which in turn can influence BMPRII expression and function. From these studies one could surmise that caveolin-1 and BMPRII cooperate to maintain vascular health.…”

“…All arteries exhibiting vWF loss had endothelial caveolin-1 loss, but all arteries exhibiting caveolin-1 loss did not have vWF loss. Importantly, at 2 wk post-MCT, there was no loss of vWF (49) or any evidence of enhanced expression of caveolin-1 in SMCs. Loss of vWF, indicative of progressive endothelial damage and extensive EC damage and/or loss, is followed by enhanced caveolin-1 expression in SMCs as…”

“…In addition, at 1 wk post-MCT before the development of PH, progressive activation of PY-STAT3 and increased expression of Bcl-xL occur (48,78). At 2 wk post-MCT, there is evidence of PH and right ventricular hypertrophy; only 26 Ϯ 3% of the arteries exhibit the presence of endothelial caveolin-1 compared with the controls with intact endothelial caveolin-1 in 100% of arteries (49). Immunofluorescence studies revealed the expression of PY-STAT3 and proliferating cell nuclear antigen in pulmonary arterial ECs with significant reduction in caveolin-1 expression (78), supporting the view that the loss of endothelial caveolin-1 is associated with the reciprocal activation of proliferative pathways.…”

“…In the MCT model of PH, enhanced expression of caveolin-1 in SMCs is accompanied by a significant increase in the expression and the activity of matrix metalloproteinase (MMP) 2 (49). SMCs from patients with idiopathic PAH also exhibit increased MMP2 activity (70), which may facilitate extracellular matrix degradation, cell migration, and eventual neointima formation.…”

Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

“…Cav1 also interacts with and regulates numerous ion channels and membrane-bound enzymes, notably endothelial nitric oxide synthase (eNOS) (for review, see Reference 10). Progressive loss of Cav1 is observed with PAEC damage in rats that acquire pulmonary hypertension (PH) after injection of monocrotaline (11) and administration of Cav1 peptides reverses PH (12). Cav1 knockout mice have PH associated with pulmonary vascular abnormalities, including loss of DPAs (13).…”