COORDINATE GENE-EXPRESSION DURING NEONATAL RAT-HEART DEVELOPMENT - A POSSIBLE ROLE FOR THE MYOCYTE IN EXTRACELLULAR-MATRIX BIOGENESIS AND CAPILLARY ANGIOGENESIS

Objective: Neonatal heart development is a period of active extracellular matrix deposition and capillary angiogenesis which follows the cessation of ventricular myocyte proliferation The aim was to determine whether coordinate expression of growth factors by the ventricular myocyte could function to inhibit myocyte proliferation directly as well as indirectly by paracrine stimulation of non-myocyte extracellular matrix deposition and capillary angiogenesis. Methods: Immunohistochemistry and northern blot hybridisations were performed on ventricular samples from fetal to mature animals of the spontaneously hypertensive (SHR) and normotensive control Wistar Kyoto (WKY) strains. Results: Ventricular expression of types I, III, and IV collagen genes reached their ''maximum'' within the first 2-3 postnatal weeks and then rapidly declined. Expression of TGFbeta3 and SPARC were found to precede and accompany the changes in extracellular matrix gene expression during this same developmental period. TGFbeta3 was immunolocalised to fetal cardiomyocytes with very limited expression in neonatal/adult non-myocytes. Associated with the neonatal expression of TGFbeta variants, transcripts for the type 2 IGF receptor gradually declined over the first three postnatal weeks. Myocyte TGFbeta gene expression, latent TGFbeta release, and paracrine mechanisms of action could be facilitated by residual type 2 IGF receptor expression to help mediate stimulation of non-myocyte extracellular matrix synthesis and deposition. Conclusions: Expression of select growth factors, growth factor receptors, and components of the extracellular matrix appear to be highly coordinated during ventricular remodelling which occurs during neonatal heart development. A paradigm is presented which integrates the expression patterns of various myocyte derived stimuli and their postulated impact on formation of the structural components of the neonatal heart by modulation of myocyte and non-myocyte cell types.