The role of plasminogen activator inhibitor-1 as inhibitor of platelet and megakaryoblastic cell adhesion.
In the present study the ability of plasminogen activator inhibitor type-1 (PAI-1) to interfere with platelet and megakaryoblastic cell adhesion was investigated. Both cell types exhibited integrin-dependent adhesion in a static system, mediated by alphaIIb beta3 on platelets and alpha v-integrins on different megakaryoblastic cell lines, even though they also expressed alphaIIb beta3. In a concentration-dependent manner, active, but not latent or complexed, PAI-1 abrogated cell adhesion onto vitronectin but not onto fibrinogen or other matrix substrata. Urokinase as well as thrombin neutralized the anti-adhesive effect of active PAI-1. The direct binding of vitronectin, but not of other matrix proteins, to integrin alphaIIb beta3 was blocked by active PAI-1 in a purified system. Since activated platelets release active and latent PAI-1 as well as structurally and functionally distinct forms of vitronectin, the described interactions appear to be physiologically significant. Co-distribution of vitronectin and PAI-1 at sites of fibrin polymers within platelet thrombi was demonstrated by transmission electron microscopy, suggesting an extracellular functional relationship of both release products with regard to cell adhesion. Our data emphasize the regulatory role of active PAI-1 in platelet adhesion to provisional matrix proteins as found during wound healing independent of its anti-proteolytic activity. Furthermore, megakaryocyte maturation may depend on the intact vitronectin-integrin adhesion system that is influenced by PAI-1, thereby proposing a regulatory role for the inhibitor in cellular differentiation.
Wohn
K D
KD
Haemostasis Research Unit, Max-Planck-Institut, Kerckhoff-Klinik, Bad Nauheim, Germany.
Schmidt
T
T
Kanse
S M
SM
Yutzy
B
B
Germer
M
M
Morgenstern
E
E
Preissner
K T
KT
D001792:Blood Platelets / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019096:Vitronectin / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019096:Vitronectin; D005337:Fibrin; D005340:Fibrinogen