Key result
Germline deletion of Col1a2 in mice increased the ventricle weight-to-body weight ratio by more than 25% at 3 months of age, leading to progressive cardiomyopathy, whereas acute fibroblast-specific deletion initially inhibited cardiomyocyte hypertrophy during pressure overload.
Why the study?
Although defects in fibroblast activity alter cardiomyocyte hypertrophy during disease stimulation, the role of collagen in communication between cardiomyocytes and fibroblasts remains unknown.
Does deletion of type I collagen (Col1a2) in cardiac fibroblasts affect cardiomyocyte hypertrophy and cardiac fibrosis in mice?
Does deletion of type I collagen (Col1a2) in cardiac fibroblasts affect cardiomyocyte hypertrophy and cardiac fibrosis in mice?
Type I collagen production by cardiac fibroblasts dynamically regulates extracellular matrix expansion and cardiomyocyte hypertrophy during pressure overload.
Supports distinct Col1a2 roles in development versus acute overload in mice; leaves open selective fibroblast targeting in human pressure-overload disease.
Rationale Cardiomyocytes and fibroblasts in the heart communicate through both secreted growth factors as well as through sensing the structural properties of the extracellular matrix that each helps generate. Previous studies have shown that defects in fibroblast activity during disease stimulation result in altered cardiomyocyte hypertrophy, although the role that collagen might play in this communication is unknown. Objective Here we investigated how type I collagen maturation and disease-responsive matrix expansion in the heart by cardiac fibroblasts impacts cardiac fibrosis and cardiomyocyte hypertrophy. Methods and Results We generated and characterized Col1a2 -/- mice using standard gene-targeting. Col1a2 -/- mice were viable, although by young adulthood their hearts showed alterations in extracellular matrix mechanical properties, as well as an unanticipated activation of cardiac fibroblasts and induction of a progressive fibrotic response. This included increases in fibroblast number and a progressive cardiac hypertrophy, with reduced functional performance by 9 months. Col1a2-loxP targeted mice were also generated and crossed with the tamoxifen-inducible Postn-MerCreMer knock-in mice to delete the Col1a2 gene in myofibroblasts post-pressure overload injury, to more specifically implicate fibroblasts as effectors of cardiomyocyte hypertrophy in vivo. Opposite to the gradual induction of cardiac hypertrophy observed in germline Col1a2 -/- mice as they matured developmentally, adult fibroblast-specific deletion of Col1a2 during pressure overload protected these mice from cardiac hypertrophy in the first week with a delayed fibrotic response. However, this reduction in hypertrophy due to myofibroblast-specific Col1a2 deletion was gradually lost over 2 and 6 weeks of pressure overload as augmented fibrosis returned. Conclusions Defective type I collagen in the developing heart alters the structural integrity of the extracellular matrix that leads to fibroblast expansion, activation, fibrosis and hypertrophy with progressive cardiomyopathy in adulthood. However, acute deletion of type I collagen production for the first time in the adult heart during pressure overload prevents ECM expansion and inhibits cardiomyocyte hypertrophy, while gradual restoration of fibrosis again permitted hypertrophy comparable to controls.
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Meng et al. (2022) studied Cardiac hypertrophy and fibrosis. Col1a2 gene deletion vs. Col1a2+/- or wild-type littermates was evaluated on Ventricle weight-to-body weight ratio. Germline deletion of Col1a2 in mice increased the ventricle weight-to-body weight ratio by more than 25% at 3 months of age, leading to progressive cardiomyopathy, whereas acute fibroblast-specific deletion initially inhibited cardiomyocyte hypertrophy during pressure overload.
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