All-trans retinoic acid modulates microvascular endothelial cell hemostatic properties.
OBJECTIVE
All-trans retinoic acid (ATRA) is an anti-tumor agent capable of controlling the hypercoagulable state associated with malignancy. Among hemostasis-regulating functions, ATRA modulates the procoagulant and fibrinolytic properties of endothelial cells (EC) from large vessels (HUVEC). In this study we investigated whether ATRA may affect the same activities of EC derived from microvessels (HMEC-1 cell line).


METHODS
We studied the effects of ATRA on procoagulant (i.e. tissue factor, TF), fibrinolytic (i.e. tissue plasminogen activator and inhibitor, t-PA and PAI-1) and anticoagulant (i.e. thrombomodulin, TM) properties of HMEC-1, compared to HUVEC. The type of retinoic acid receptor (RAR) possibly involved was identified by using synthetic retinoid selective agonists or antagonists for RAR alpha, beta or gamma. The study was conducted with or without tumor necrosis factor (TNF)alpha to induce the expression of some endothelial hemostatic properties.


RESULTS
ATRA significantly inhibited TNFalpha-induced TF expression in HMEC-1 as well as HUVEC. ATRA increased t-PA antigen without significantly affecting PAI-1 expression, and counteracted the TNFalpha-induced t-PA decrease in both types of EC. Accordingly, t-PA activity was significantly increased by ATRA, even in the presence of TNFalpha. Finally, ATRA upregulated TM, and prevented TNFalpha-induced TM downregulation. The study with selective RARs agonists and antagonists indicated that RARalpha played a major role in t-PA and TM modulation, whereas all three receptors were involved in TF downregulation.


CONCLUSIONS
This study provides the first evidence that ATRA increases antithrombotic potential also in microvascular EC, a very relevant compartment for tumor- and/or antitumor therapy-associated vascular complications.
Marchetti
Marina
M
Hematology Department, Ospedali Riuniti Bergamo, Largo Barozzi, 1, 24128 Bergamo, Italy.
Vignoli
Alfonso
A
Bani
Maria Rosa
MR
Balducci
Donatella
D
Barbui
Tiziano
T
Falanga
Anna
A
D001565:Benzoates / Q000494:pharmacology; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology / Q000821:virology; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology; D006487:Hemostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D000072482:Retinoic Acid Receptor alpha; D013539:Simian virus 40; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000821:virology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D018180:Thrombomodulin / Q000096:biosynthesis; D013925:Thromboplastin / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D001565:Benzoates; D017395:Plasminogen Activator Inhibitor 1; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C068073:Am 580; D014212:Tretinoin; D013925:Thromboplastin; D010959:Tissue Plasminogen Activator