Role of proteolysis and apoptosis in regression of pulmonary vascular remodeling

Remodeled pulmonary arteries return to normal structural conditions after t he increase in pulmonary artery flow resistance is reversed. We studied whe ther proteolysis of extracellular matrix proteins and apoptosis occur durin g reversal of remodeling produced by chronic hypoxia in the rat. Main pulmo nary arteries were removed at different times during a 10-day period of exp osure to 10% O-2 and 14 days after return to air. Content and rates of degr adation of collagen and elastin as well as immunoreactive collagenase in ti ssue and isolated mast cells were measured. Immunoblots for collagenase and tissue inhibitor of metalloproteinases (TIMP) were performed. Apoptosis wa s 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 day s of air. Transient increases in collagenolytic and elastolytic enzyme acti vities accompanied the rapid decrease in matrix proteins. Mast cells contai ning collagenase accumulated in remodeled pulmonary arteries, and the activ e form of collagenase appeared at the time of peak proteolytic activity. TI MP increased during remodeling. Apoptosis was maximal 3 days after return t o air. Our results suggest that activation of enzymes, which degrade matrix proteins, and apoptosis play a role in resolution of vascular remodeling.