Summary
Matrix metalloproteinase-2 (MMP-2, gelatinase A) and thrombin contribute to many long-term
(patho)physiological processes requiring the proteolytic breakdown of the vascular
extracellular matrix (e.g., normal tissue repair, remodeling, tumor invasion, atherosclerosis
plaque rupture). Thrombin (10 to 1000 nM, 0.5 to 50 U/ml) induced a rapid secretion
of MMP-2 from freshly isolated rat aortic tissue (detectable after 1 min of thrombin
exposure). This secretion was mediated by an unidentified thrombin receptor, distinct
from the proteinase activated receptors (PAR)-1 and -2. Protein tyrosine kinase/phosphatase
activity differentially modulated the basal and the thrombin-induced release of MMP-2.
The inhibitors of protein tyrosine kinase, herbymicin A, genistein, and tyrphostin
1288 (1 to 100 μM), enhanced the basal release of MMP-2 but did not affect the thrombin-induced
secretion of MMP-2. The inhibitor of phosphotyrosine phosphatases, vanadate (100 μM),
selectively inhibited the thrombin-induced, but not the basal, release of MMP-2. Rapid
release of vascular MMP-2 by thrombin could contribute to short-term processes where
thrombin is involved such as the regulation of platelet aggregation and vascular reactivity.
Vascular tyrosine kinase/phosphatase likely modulates this action of thrombin to prevent
exaggerated platelet aggregation, thrombosis, and vasospasm.
