Role of Proteolysis and Apoptosis in Regression of
Pulmonary Vascular Remodeling
D. J. Riley1, S. Thakker-Varia1, F. J. Wilson2,
G. J. Poiani1,3,
C. A. Tozzi1,3
1Departments of Medicine and 2Neuroscience and Cell Biology,
University of Medicine and Dentistry of New Jersey - Robert Wood Johnson Medical
School, Piscataway, New Jersey,
3VA New Jersey Health Care System, Lyons, New Jersey, USA
Received February 22, 2000
Accepted April 3, 2000
Summary
Remodeled pulmonary arteries return to normal structural
conditions after the increase in pulmonary artery flow resistance is reversed.
We studied whether proteolysis of extracellular matrix proteins and apoptosis
occur during reversal of remodeling produced by chronic hypoxia in the rat. Main
pulmonary arteries were removed at different times during a 10-day period of
exposure to 10% O2 and 14 days after return to air. Content and rates
of degradation of collagen and elastin as well as immunoreactive collagenase in
tissue and isolated mast cells were measured. Immunoblots for collagenase and
tissue inhibitor of metalloproteinases (TIMP) were performed. Apoptosis was
assessed by cleavage of DNA and TUNEL assay. Excess collagen and elastin present
at 10 days of hypoxia decreased to near normal levels after 3-5 days of air.
Transient increases in collagenolytic and elastolytic enzyme activities
accompanied the rapid decrease in matrix proteins. Mast cells containing collagenase accumulated in remodeled pulmonary arteries, and the active form of collagenase appeared at the time of peak proteolytic activity. TIMP increased
during remodeling. Apoptosis was maximal 3 days after return to air. Our results
suggest that activation of enzymes, which degrade matrix proteins, and apoptosis
play a role in resolution of vascular remodeling.
Key words
Vascular remodeling · Apoptosis ·
Matrix metalloproteinase · Hypertension ·
Pulmonary
Reprint requests
David J. Riley, M.D., Department of Medicine, UMDNJ-Robert
Wood Johnson Medical School, Room C-B04, 675 Hoes Lane, Piscataway, NJ
08854-5635 USA, e-mail: riley@umdnj.edu
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