Abstract
Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis. Amongst these factors is the angiogenesis inhibitor angiostatin, which is released during thrombus formation. The impact of anti-thrombotic agents and the kinetics of platelet angiostatin release are unknown. Hence, our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration, an early stage of angiogenesis. We hypothesized anti-platelet agents would suppress angiostatin release but not generation by platelets. Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor (VEGF). Immuno-gold electron microscopy and immunofluorescence microscopy identified α-granules as storage organelles of platelet angiostatin. Acetylsalicylic acid, MRS2395, GPIIb/IIIa blocking peptide, and aprotinin were used to characterize platelet angiostatin release and generation. An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition. Compared to VEGF, angiostatin generation and release from α-granules occurred later temporally during platelet aggregation. Consequently, collagen-activated platelet releasates stimulated endothelial cell migration more potently than maximally-aggregated platelets. Platelet inhibitors prostacyclin, S-nitroso-glutathione, acetylsalicylic acid, and GPIIb/IIIa blocking peptide, but not a P2Y12 inhibitor, suppressed angiostatin release but not generation. Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet-stimulated endothelial migration. Hence, the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo-vascularization following thrombus formation.
Highlights
Platelets are well known to contribute to the promotion of new blood vessel growth and do so by releasing a large repertoire of angiogenesis promoting factors largely from their a-granules [1,2]
We hypothesized that perhaps the differential storage of angiostatin from that of vascular endothelial growth factor (VEGF) may explain the differences in temporal release of the two angiogenesis regulators
Anti-platelet Factors Prevent Angiostatin Release Because platelet aggregation and thrombus formation are inhibited by physiological factors such prostacyclin (PGI2), nitric oxide (NO) and by pharmacological anti-platelet agents [23], we investigated the effects of platelet inhibition on angiostatin release
Summary
Platelets are well known to contribute to the promotion of new blood vessel growth and do so by releasing a large repertoire of angiogenesis promoting factors largely from their a-granules [1,2]. Included amongst these angiogenesis promoters is vascular endothelial growth factor, one of the most potent endothelial cell growth and survival factors [3,4]. In addition to being formed by cancer and inflammatory cells [7], angiostatin is present in healthy humans It is found in abundance in human plasma [8], and it is constitutively generated by platelets and released in active form upon aggregation [5,8,9]
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