Physiol. Res. 49: 577-585, 2000

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


© 2000 by the Institute of Physiology, Czech Academy of Sciences