Contraction of Human Brain Endothelial Cells Induced by Thrombogenic and Fibrinolytic Factors

[Guest guest]

Ken,

I'd like your opinion on the article below, if you have time to comment at least

on the bit I am quoting here.

Thanks

Nelly

Contraction of Human Brain Endothelial Cells Induced by Thrombogenic and

Fibrinolytic Factors

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The interactions of plasmin with endothelial cells of diverse origin are well

characterized in terms of binding constants.12 13 In our study endothelial cells

from human brain capillaries contracted in the course of plasmin treatment. This

response of the endothelium may be the basis of brain edema after thrombolytic

treatment in ischemic stroke. If the administered plasminogen activators

(streptokinase, urokinase, or tissue-type plasminogen activator) generate high

concentrations of plasmin, ***the enzyme will bind not only to its substrate

(fibrin) and its plasma inhibitors but also to the capillary endothelium. The

consequent cell contraction would increase the permeability of the BBB***.

6-Aminohexanoate is clinically used as an antifibrinolytic drug because of its

well-known property of blocking the interactions of plasmin kringle domains with

lysine residues on fibrin.29 30 In the presence of 6-aminohexanoate the

plasmin-induced cell contraction is substantially diminished. This observation

implies a role for the kringle domains in the interactions of plasmin and

endothelial cells.

Of the two plasminogen activators (urokinase, streptokinase), only urokinase

induces cell contraction. Thus, all of the proteases used here contract the

brain endothelial cells, whereas proteins that possess no proteolytic activity

(eg, fibrinogen, antithrombin, and streptokinase [the latter is frequently used

in fibrinolytic therapy]) have no effect on the cell morphology. When the active

center of the enzymes is blocked by a protease inhibitor (antithrombin III),

cell contraction is essentially negligible, suggesting the involvement of the

active center in the effects of the enzymes on the endothelial cells.

Fibrin is known to cause changes in the morphology of endothelial cells31 and

possibly contributes to the increase in the permeability of the pulmonary

microvasculature in thromboembolic injury.32 These observations are in agreement

with our findings in human brain microvessel endothelial cell culture. The fact

that the lowest concentration of fibrin produces the most pronounced effect

strongly suggests that thrombin (present in all fibrin gels at the same

concentration and potentially released from its substrate) is responsible for

the cell contraction rather than the fibrin itself. The elucidation of this

question requires further experiments. On the other hand, fibrin reduces the

effects of plasmin on the endothelial cells (Table), presumably because of the

higher affinity of plasmin to its substrate (fibrin) than to the cell receptors.

Simultaneously plasmin digests fibrin, and as a result the effect of fibrin and

plasmin together is less than that of either agent alone. (...)