Role of transforming growth factor β1 as modulator of endothelial L-Arginine/ nitric oxide signalling pathway

Abstract

TGF-β is one of the members of the TGF-β superfamily of growth factors, including activins/inhibins and bone morphogenic proteins (BMP). At least three TGF-β isoforms have been reported in mammals: TGF-β1, TGF-β2 and TGF-β3. Virtually all human cells produce TGF-β and express its plasma membrane receptors. Each isoform is coded by a different gene, in a tissue-specific and developmental-regulated manner. TGF-β1 mRNA is expressed in endothelial, haematopoietic and connective-tissue cells, TGF-β2 mRNA is expressed in epithelial and neuronal cells, and TGF-β3 mRNA in mesenchymal cells (1,3,25). The sequence homology is 70-80% between TGF-β isoforms and 30-40% with activins/inhibins and BMP. TGF-β1, 2 and 3 are highly conserved in mammals suggesting a critical biological function for each of these isoforms, acting as strong mediators of tissue repair through chemotaxis and angiogenesis stimulation and extracellular matrix generation (1,3,25). TGF-β1 is a 112 amino acid polypeptide which forms a homodimer with both subunits linked with a disulfide bond. TGF-β1 is synthesized as a precursor of 391 amino acids whose amino acid sequence includes TGF-β1 and the propeptide latencyassociated peptide (LAP) in the amino terminal. TGF-β1 is cleaved from LAP before the precursor is secreted from the cells, but it continues non-covalently bond to this propeptide. After being secreted, TGF-β1 is stored at the extracellular matrix as a complex formed between TGF-β1, LAP and the latent TGF-b binding protein (LTBP). The relation between TGF-β1 and LTBP through disulfide bond prevents the binding of TGF-β1 to its receptors. In vivo, TGF-β1 is released from the complex by the matrix glycoprotein thrombospondin 1 (TSP-1), which changes the conformation of LTBP (1,25).