Role of extracellular retention of platelet-derived growth factor-B. Functions in development and disease

Sammanfattning: During development, the cell secretes growth and differentiation factors (GDFs) to the surrounding microenvironment. These factors are often key regulators of organogenesis and embryogenesis. Several GDFs carry sequences that mediate specific interaction with molecules of the extracellular matrix (ECM) that surrounds the cell. The deposition of factors in the matrix can theoretically result in (1) reservoirs of growth factors, (2) in spatially restricted action range of the factor or (3) in the critical growth factor concentrations or gradients needed for the factor to elicit specific cellular responses i.e. to act as a morphogen. So far, few attempts have been made to analyse the functional importance of GDF-ECM interactions. Several platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) family members display basic amino acid motifs at the C-terminus, which confer retention of the factor in the extracellular milieu surrounding the producing cell. To address the role of PDGF-B retention in vivo, we deleted the retention motif in mice by a gene targeting approach. This resulted in reduced recruitment and defective investment of pericytes in the micro-vessel wall, and in delayed formation of the glomerular mesangium. Long-term effects of lack of PDGF-B retention included reactive gliosis in the CNS, severe retinal detoriation, glomerulosclerosis and proteinuria. Several tumours express PDGF-B and the cognate receptor PDGFR-b. To investigate the effects of altered PDGF-B distribution in a pathological situation, we analysed the vasculature in a tumour model. In tumours transplanted to PDGF retention deficient mice, pericytes were fewer and partially detached, leading to significantly increased vessel diameter and haemorrhaging. Tumour specific over-expression of PDGF-B increased the pericyte density in both control and in PDGF-B retention deficient mice, but could not correct the defective pericyte integration in the vascular wall. To analyse developmental effects of PDGF over-expression, we generated transgenic mice that over-expressed different PDGF isoforms specifically in the heart. This caused pathological changes ranging from severe and generalised cardiac fibrosis and early postnatal lethality to focal fibrosis in the adult heart. Thus, PDGF signalling seems sufficient to induce cardiac fibrosis. In conclusion, the alteration of PDGF distribution or increased/decreased PDGF levels, have detrimental effects during development, as well as in the adult. The results point to an important role for PDGF in cancer and on retinal, glomerular and myocardial diseases.