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Altered hemodynamics controls matrix metalloproteinase activity and tenascin-C expression in neonatal pig lung
Peter Lloyd Jones1, Rene Chapados, H Scott Baldwin
1Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Peter.Jones@UCHSC.edu
Insights
Altered pulmonary blood flow increases Tenascin-C (TN-C) and matrix metalloproteinase (MMP) expression in pulmonary arteries. This suggests a mechanism linking hemodynamic changes to vascular remodeling in congenital heart defects.
Area of Science:
- Cardiovascular Research
- Pulmonary Hypertension
- Developmental Biology
Background:
- Tenascin-C (TN-C) and matrix metalloproteinases (MMPs) are implicated in pulmonary artery (PA) remodeling.
- Pulmonary vascular disease in congenital heart defects often involves altered pulmonary hemodynamics.
Purpose of the Study:
- To investigate if changes in pulmonary blood flow regulate TN-C and MMPs in neonatal pigs.
- To elucidate the molecular mechanisms linking hemodynamic changes to PA remodeling.
Main Methods:
- Neonatal pigs underwent left PA ligation to modify pulmonary hemodynamics.
- TN-C and MMP levels, Egr-1 activity, and cell behavior on collagen substrates were evaluated.
- Porcine PA smooth muscle cells were cultured on native and denatured type I collagen.
Main Results:
- Pulmonary artery ligation significantly increased TN-C mRNA and protein expression.
- MMP activity and Egr-1 DNA-binding activity were elevated in ligated PAs.
- Culturing PA smooth muscle cells on denatured collagen enhanced TN-C expression and Egr-1 activity.
Conclusions:
- Hemodynamic changes in pulmonary blood flow can directly regulate TN-C and MMP expression in PAs.
- Egr-1 plays a crucial role in mediating the effects of altered hemodynamics on TN-C expression.
- These findings provide a framework for understanding neonatal pulmonary vascular remodeling in response to hemodynamic alterations.
Abstract:
Tenascin-C (TN-C) expression and matrix metalloproteinase (MMP) activity are induced within remodeling pulmonary arteries (PAs), where they promote cell growth. Because pulmonary vascular disease in children with congenital heart defects is commonly associated with changes in pulmonary hemodynamics, we hypothesized that changes in pulmonary blood flow regulate TN-C and MMPs. To test this, we ligated the left PAs of neonatal pigs. After 12 wk, we evaluated the levels of TN-C and MMPs in control and ligated lung tissue. Modifying pulmonary hemodynamics increased TN-C mRNA and protein expression, MMP activity, and the DNA-binding activity of Egr-1, a transcription factor that has been shown to activate TN-C expression. To link MMP-mediated remodeling of the extracellular matrix to increased TN-C expression and Egr-1 activity, porcine PA smooth muscle cells were cultivated either on denatured type I collagen, which supported TN-C expression and Egr-1 activity, or on native collagen, which had the opposite effect. These data provide a framework for understanding how changes in pulmonary blood flow in the neonate modify the tissue microenvironment and cell behavior.