Urokinase Plasminogen Activator Colocalizes with CD25+ Cells in Atherosclerotic Vessels

Abstract

Proteolytic activity in vascular tissue is necessary for cellular migration, remodelling of extracellular matrix and the development of atherosclerotic lesions. Inflammatory cells, mainly macrophages, are numerous in atherosclerotic plaques and may synthesize and secrete proteolytic enzymes. The principal activator of plasminogen in tissues is urokinase plasminogen activator (u-PA). To determine if an activated phenotype of inflammatory cells colocalizes with local expression of u-PA in atherosclerotic vessels, vascular biopsies from 15 patients with peripheral atherosclerotic disease were analyzed by immunohistochemistry on consecutive sections. Anti-CD68 antibodies were used as markers for macrophages and were positive in 14/15 specimens. Anti-CD25 (interleukin-2 receptor-α) antibodies were used to identify inflammatory cells with an activated phenotype and were positive in 9/14 CD68+ specimens. The same 9 specimens were positive for u-PA. A positive reaction for u-PA was found only in specimens with CD25+ cells. Specimens with positive reactions for all three antibodies were further analyzed with computer-assisted image analysis. The colocalization with u-PA was higher for CD25 compared to CD68 in all specimens. Mean percentage of the u-PA-positive area in regions positive for cellular markers was 52% (SEM 6%) for CD25 and 19% (SEM 5%) for CD68 (p < 0.01). The results indicated that the activation of macrophages in atherosclerotic vessels may modulate local proteolysis and be of importance in plaque development and stability.

Overexpression of Urokinase by Plaque Macrophages Causes Histological Features of Plaque Rupture and Increases Vascular Matrix Metalloproteinase Activity in Aged Apolipoprotein E–Null Mice

“…uPA is highly expressed in macrophage-rich areas adjacent to the shoulder regions of advanced human atherosclerotic lesions 16, 17, 38. “Culprit” human carotid plaques have increased expression of plasminogen activators and elevated plasmin activity compared to uncomplicated plaques,39 and both elevated plasminogen activator mRNA and increased uPA receptor expression by macrophages correlate with intraplaque hemorrhage and rupture in acutely symptomatic human carotid plaques 40, 41.…”

“…Some MMPs are activated within the secretion pathway by proprotein convertase; however, for most MMPs, including essentially all MMPs implicated in plaque rupture, the activation mechanism is unknown 15. Plasmin, an abundant serine proteinase that could be activated within the plaque by macrophage-expressed urokinase plasminogen activator (uPA),16, 17 is often considered to be a critical activator of MMPs in the vessel wall 18, 19…”

Identification of Diagnostic Biomarkers for Infection in Premature Neonates

“…Other studies have reported additional links between the above molecules, e.g. colocalization of neutrophil elastase, uPA, and uPAR (72) or colocalization of uPA and IL-2sR␣ (73). Finally pathogens are known to interact in a specific manner with components of fibrinolytic pathways as well as with CRP (74).…”

The role of inflammation in vascular diseases

“…2A) The presence of inflammatory cells in diseased blood vessels does not imply that these cells are necessarily activated. There is evidence that there are subpopulations of activated and non-activated macrophages [29,59] and T cells [60] within plaques. Within the vascular wall, activated immune cells influence blood flow through the release of cell mediators.…”