Investigational approaches to pulmonary hypertension.
Pulmonary vascular disease (PVD) revolves around a series of switches in the smooth muscle cell (SMC) phenotype. Differentiation of SMC from precursor cells causes muscularization of normally non-muscular peripheral arteries; hypertrophy and hyperplasia of existing SMC and increased connective tissue protein synthesis cause thickening of the wall, and migration of SMC into the subendothelial space is the basis of intimal proliferation. To uncover the pathophysiologic mechanisms of these changes, we have used a variety of animal models and cell culture systems. From rats in which hypertensive PVD was induced by exposure to chronic hypoxia or following injection of the pyrrolizidine alkaloid, monocrotaline, we have identified increased pulmonary artery (PA) elastolytic activity which occurs early and which accompanies progressive rather than reversible PVD. Inhibition of elastolytic activity prevents or reduces PVD. We are cloning the gene for this new enzyme to study its regulation in PVD. To address the mechanism of SMC proliferation under conditions of high PA pressure and flow, we cultured endothelial cells on polyvinylchloride membranes and pulsated them at high pressure. This caused reduced synthesis of heparan sulfate. The resulting decrease binding of fibroblast growth factor would lessen its mitogenic effect and modulate SMC proliferation in response to other growth factors from platelets or serum. To study SMC migration, we cultured endothelial and SMC from the ductus arteriosus (a fetal vessel which spontaneously develops intimal proliferation in late gestation). The migratory SMC phenotype is a function of increased production of fibronectin governed by a translational control mechanism, and increased endothelial hyaluronan regulated by transforming growth factor beta. SMC migration is also related to impaired assembly of elastin, the result of a chondroitin sulfate-induced decrease in elastin binding proteins and the production of a novel 'defunct' 52 kD tropoelastin.
Rabinovitch
M
M
University of Toronto, Hospital for Sick Children, Ontario, Canada.
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D004373:Ductus Arteriosus / Q000166:cytology / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology; D009130:Muscle, Smooth / Q000166:cytology