Objective: Our objective was to elucidate the role of caveolin-1 in human pulmonary hypertension (PH). We have previously shown that monocrotaline (MCT)-induced PH in rats is preceded by a progressive reduction in endothelial caevolin-1 expression and rescue of caveolin-1 attenuates PH. Caveolin-1, a major scaffolding protein of caveolae found on most cells including endothelial and smooth muscle cells (SMCs), interacts with several signaling molecules, and it inhibits cell proliferation.

Methods: Histology, pulmonary arterial medial thickness; and endothelial cell membrane integrity and caveolin-1 expression using immunofluorescence technique were examined in lung biopsy specimens from children with PH (n= 6). In addition, rats were given 60 mg/kg MCT and examined 2 and 4 wks post-MCT to evaluate PH and the expression of proteins of interest.

Results: Clinical PH revealed not only loss of endothelial caveolin-1 but also caveolin-1 expression in SMCs. Neointima formation was seen in vessels with robust expression of caveolin-1 in SMCs. MCT-treated rats showed progressive PH at 2 and 4 wks post-MCT (max.systolic pressure, 40± 4 mmHg), loss of endothelial caveolin-1. However, neither caveolin-1 expression in SMCs nor neointima was observed.

Conclusions: Initial injury (mechanical or inflammatory) results in endothelial damage leading to cell proliferation and medial wall thickening. Robust expression of caveolin-1 in SMCs appears to be a prerequisite for neointima formation. It is likely that in PH, caveolin-1 in SMC switches from antiproliferative to a proproliferative molecule, therefore, the use of statins to disrupt cell membrane and inhibit proproliferative activity of caveolin-1 may be beneficial in PH.