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Departments of 1 Medicine, 2 Physiology, and 3 Pharmacology, and the 4 Program in Biomedical Engineering, State University of New York, Stony Brook, New York 11794-8152; and 5 Department of Medicine, Royal Free and University College Medical School, London WC1E 6JJ, United Kingdom
Plasminogen
activator (PA) inhibitor-1 (PAI-1) has been recognized as a surrogate
marker of endothelial dysfunction in diseases associated with impaired
angiogenesis, including atherosclerosis, diabetic vasculopathy, and
nephropathy. To establish the necessary and sufficient components of
the PA system [PAI-1, urokinase-type PA (uPA), or tissue-type PA
(tPA), and plasminogen (Plg)] for angiogenesis, we examined angiogenic
competence of vascular explant cultures obtained from mice deficient in
PAI-1, tPA, uPA, and Plg. To gain insight into the requirement for
different matrix-degrading systems during endothelial cell migration
across plasmin-degradable basement membranes compared with profibrotic
areas containing plasmin-nondegradable collagen, we contrasted vascular
sprouting in collagen with Matrigel lattices. PAI-1
/
vessels showed an increased capillary sprouting in both collagen and
Matrigel. Deficiency of uPA significantly reduced the rate of
sprouting, whereas tPA/ vessels showed a profound
inhibition of capillary sprouting. The Plg/ vessels
failed to sprout, a defect that was restored not only by exogenous Plg,
but also by the addition of PAs; a nonproteolytic effect of tPA was
observed in Matrigel. Zymography revealed no differences in the
activity of metalloproteinase (MMP)-2 and -9 in wild-type and
PAI-1/ vessels, but demonstrated reduced MMP-9 activity
in all angiogenesis-deficient vessels. In summary, 1) PAI-1
by itself is a modest inhibitor of endothelial sprouting, 2)
tPA and Plg are indispensable for angiogenesis in this model,
3) Plg is not the only substrate for PAs, and 4)
the activity of MMP-9 is undetectable in explant cultures from tPA and
Plg knockout mice.
plasminogen activator inhibitor-1; metalloproteinase
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