Conference: 2010 International PHA Conference and Scientific Sessions
Release Date: 06.24.2010
Presentation Type: Abstracts
Mathew R, Huang J, Sandoval C, Dereddy N, Katta UD, Wolk JH, Erb M, Gewitz MH.
Maria Fareri Children’s Hospital at Westchester Medical Center, NY, USA Medical College, Valhalla, NY, USA
BACKGROUND: We have previously shown that monocrotaline-induced pulmonary hypertension (PH) in rats is preceded by a progressive loss of endothelial caevolin-1, and rescue of caveolin-1 attenuates PH. Caveolin-1, a major scaffolding protein of caveolae found on most cells including endothelial (EC) and smooth muscle cells (SMC), interacts with several signaling molecules, and it inhibits cell proliferation. Recent studies have shown enhanced expression of caveolin-1 in SMC with proliferative properties facilitating DNA synthesis and cell proliferation. Our objective was to elucidate the expression of caveolin-1 in pediatric patients with PH.
METHODS: The lung sections obtained at biopsy or autopsy from 13 infants and children were evaluated for lung histology, medial wall thickness; and the expression of caveolin-1, PECAM-1, vWF and smooth muscle actin. Patients were divided into 4 groups (Gr 1, Congenital heart defect [CHD, n=4], Gr 2, Lung Disease [n=4], Gr 3, Miscellaneous [all with lung hypoplasia, n=3], Gr 4, cyclosporin toxicity [n=2]).
RESULTS: Pulmonary arteries subjected to increased shear stress secondary to increased pulmonary blood flow or drug toxicity revealed loss of endothelial cell membrane integrity, endothelial caveolin-1 and PECAM-1. Loss of vWF, indicative of extensive endothelial damage was associated with enhanced expression of caveolin-1 in SMC. In an older child, enhanced expression of caveolin-1 in SMC was followed by neointima formation. Despite increased pulmonary vascular remodeling, endothelial caveolin-1, PECAM-1 and vWF were well preserved in patients with normal pulmonary blood flow including an infant with CHD without a shunt; and there was no evidence of enhanced caveolin-1 expression in SMC.
CONCLUSIONS: Extensive EC damage results in enhanced expression of caveolin-1 in SMC leading to further cell proliferation, and possible cell migration and neointima formation. Elevated pulmonary artery pressure per se does not injure EC. A “second hit” such as shear stress, chemical toxicity or inflammation is required for EC disruption. In defects without associated increased pulmonary blood, despite medial thickening, there was no loss of endothelial caveolin-1, PECAM-1 or vWF; importantly, caveolin-1 was not detectable in SMC. Thus, the mechanism of pulmonary vascular remodeling may depend on pulmonary blood flow or on drug/inflammation-induced endothelial damage.