Altered hemodynamics controls matrix metalloproteinase activity and tenascin-C expression in neonatal pig lung.
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.
Jones
Peter Lloyd
PL
Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Peter.Jones@UCHSC.edu
Chapados
Rene
R
Baldwin
H Scott
HS
Raff
Gary W
GW
Vitvitsky
Eugene V
EV
Spray
Thomas L
TL
Gaynor
J William
JW
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D008168:Lung / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D011651:Pulmonary Artery / Q000166:cytology; D011652:Pulmonary Circulation / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D019063:Tenascin / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D019063:Tenascin; D014157:Transcription Factors; D003094:Collagen; D004247:DNA; D020782:Matrix Metalloproteinases