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Coordinate gene expression during neonatal rat heart development. A possible role for the myocyte in extracellular
1Department of Medicine, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153.
Insights
Neonatal heart development involves coordinated growth factor expression by cardiomyocytes. This study shows these factors regulate extracellular matrix deposition and angiogenesis, influencing neonatal heart remodeling.
Area of Science:
- Cardiovascular biology
- Developmental biology
- Molecular cardiology
Background:
- Neonatal heart development features significant extracellular matrix deposition and capillary angiogenesis.
- Ventricular myocyte proliferation ceases before these processes begin.
Purpose of the Study:
- To investigate if ventricular myocytes coordinate growth factor expression.
- To determine if this expression inhibits myocyte proliferation directly.
- To assess if it indirectly stimulates non-myocyte extracellular matrix deposition and angiogenesis via paracrine signaling.
Main Methods:
- Utilized immunohistochemistry and northern blot hybridizations.
- Analyzed ventricular samples from fetal to mature spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats.
Main Results:
- Type I, III, and IV collagen gene expression peaked in the first 2-3 postnatal weeks, then declined.
- Transforming growth factor-beta 3 (TGF-β3) and SPARC expression preceded and accompanied extracellular matrix gene changes.
- TGF-β3 localized to fetal cardiomyocytes; type 2 IGF receptor transcripts declined postnatally.
Conclusions:
- Growth factors, receptors, and extracellular matrix components are coordinated during neonatal ventricular remodeling.
- A model is proposed integrating myocyte-derived stimuli and their effects on neonatal heart structural development.
- This involves modulation of both myocyte and non-myocyte cell types.
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 TGF beta 3 and SPARC were found to precede and accompany the changes in extracellular matrix gene expression during this same developmental period. TGF beta 3 was immunolocalised to fetal cardiomyocytes with very limited expression in neonatal/adult non-myocytes. Associated with the neonatal expression of TGF beta variants, transcripts for the type 2 IGF receptor gradually declined over the first three postnatal weeks. Myocyte TGF beta gene expression, latent TGF beta 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.