Vascular remodeling in pulmonary hypertension

Sammanfattning: Pulmonary hypertension (PH) is a progressive obliterative vasculopathy with multifactorial etiology and high mortality rate. Endothelial dysfunction, excessive vascular remodeling, inflammation and in situ thrombosis contribute to increased vascular resistance and gradual occlusion of pulmonary vessels. Sustained high pressure in the pulmonary circulation increases right heart afterload and ultimately results in right heart failure. Current pharmacological treatments, like endothelin receptor antagonists, prostacyclin analogues, and phosphodiesterase-5 inhibitors, are primarily vasodilators and exert limited effects on vascular remodeling. Survival has improved, but far from enough, and the demand for lung transplantation has not been reduced. Excessive growth of pulmonary artery smooth muscle cells (PASMCs) contributes to intimal hyperplasia, medial wall thickening, and plexiform lesions, the main features of vascular remodeling in PH. It is therefore important to explore factors which can control PASMC growth in order to identify potential targets for regression of PH. Here, the roles of growth factors and proteoglycans in vascular remodeling were investigated in animal models of PH as well as in tissue specimens from patients. In a rat model of PH associated with congenital diaphragmatic hernia, up-regulation of PDGF-B was found. Prenatal PDGF-B inhibition by imatinib, a tyrosine kinase inhibitor, was demonstrated to inhibit PASMC proliferation and to reduce pulmonary vascular remodeling in fetal rat lungs. In a murine model of hypoxia-induced PH, increased perlecan deposition was observed. Genetically modified mice expressing heparan sulfate-deficient perlecan developed less PH, accompanied by decreased pulmonary vascular remodeling and reduced right ventricular hypertrophy. In addition, defective mural cell recruitment in pulmonary vessels was observed in heparan sulfate-deficient mice. A possible mechanism is impaired interaction between FGF-2 and its receptor and a pro-proliferative function for perlecan heparan sulfate in pulmonary vessels. The role of PDGF-B retention motifs, the C-terminal region of PDGF-B that interacts with heparan sulfate, was also explored. Hypoxia-induced PH was reduced in PDGF-B retention motif knockout, possibly due to defective retention of PDGF-B in the extracellular matrix and disturbed recruitment of mural cells. Metabolic labeling experiments showed that a majority of the proteoglycans secreted by human PASMCs are decorated with chondroitin sulfate. Lung tissue sections from patients with PH revealed versican accumulation in vascular lesions. In vitro, mechanical strain and hypoxia increased versican production in PASMCs. The results suggested that versican is a pro-proliferative element in the vascular remodeling of PH. In summary, this thesis work emphasizes the role of growth factors and proteoglycans, and interactions between the two, in the regulation of PASMC growth during PH development. Inhibition of growth factor activity or specific targeting of important functional domains of proteoglycans may be effective anti-remodeling strategies for future PH treatment.