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Updated: Mar 12, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice
Radiosa Gallini1, Per Lindblom2, Cecilia Bondjers2
1Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Insights
Platelet-derived growth factors (PDGFs) play a role in heart development. Overexpression of PDGF-A in mice caused severe cardiac fibrosis and failure, while PDGF-B caused moderate effects, highlighting isoform-specific impacts.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Molecular Cardiology
Background:
- Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are crucial for normal heart development.
- Dysregulation of PDGF/PDGFR signaling negatively impacts cardiac development and function.
- The specific cellular effects and pathogenesis of PDGFs in cardiac abnormalities are not fully understood.
Purpose of the Study:
- To investigate the isoform-specific effects of PDGF ligands on cardiac development and function.
- To elucidate the cellular mechanisms underlying PDGF-induced cardiac fibrosis and hypertrophy.
- To determine the role of specific PDGFRs in mediating these effects.
Main Methods:
- Generation of three new transgenic mouse models expressing PDGF-A and PDGF-B under a heart-specific promoter.
- Analysis of cardiac histology, fibrosis, and hypertrophy in response to PDGF isoform overexpression.
- Assessment of PDGFR expression and correlation with fibrotic reactions.
Main Results:
- Transgenic PDGF-A overexpression led to severe cardiac fibrosis, an 8-fold increase in heart size, and lethal cardiac failure.
- Transgenic PDGF-B overexpression resulted in focal fibrosis and moderate cardiac hypertrophy.
- PDGF-A-induced fibrosis was primarily mediated by PDGFR-alpha in cardiac interstitial mesenchymal cells.
Conclusions:
- PDGF-A and PDGF-B isoforms exert distinct effects on cardiac structure and function.
- PDGFR-alpha signaling in cardiac interstitial mesenchymal cells is a key mediator of PDGF-A-induced cardiac fibrosis.
- The heart's sensitivity to PDGFR-alpha agonists suggests a role for endogenous agonists in cardiac fibrosis pathogenesis.
Abstract:
Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfrα in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFRα agonists supports a role for endogenous PDGFRα agonists in the pathogenesis of cardiac fibrosis.
