Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release

Abstract

Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcerassociated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.angiogenesis ͉ ticlopidine ͉ aspirin ͉ proliferation ͉ endothelium

Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist

“…It is most likely that the release of those factors is due to degranulation during platelet activation and therefore parallels the extent of aggregation (Linder et al, 1979). However, although thrombin and ADP induced a similar extent of platelet aggregation in our previous study (Ma et al, 2001), only thrombin stimulated platelet endostatin release, suggesting that endostatin is unlike those growth factors that are stored in alpha granules and released in accordance with the extent of platelet aggregation. Furthermore, it has been found that in rat platelets, which do not possess PAR1, the PAR4 activating peptide AY-NH 2 stimulated platelet aggregation (Hollenberg & Saifeddine, 2001) and endostatin release in the same manner as thrombin.…”

“…Endostatin, a potent inhibitor of angiogenesis (O'Reilly et al, 1997), has been shown recently to be contained within platelets and to be released in response to thrombin but not to ADP (Ma et al, 2001).…”

“…Moreover, endostatin released from platelets was found to play a signi®cant role in modulating gastric ulcer healing in the rat (Ma et al, 2001). However, the mechanism through which thrombin produces this e ect, and in particular the PAR receptor involved, are unknown.…”

“…Platelet aggregation and endostatin release was studied in response to thrombin and PAR4 activating peptide ex vivo (Wallace et al, 1995;Ma et al, 2001). Aliquots (0.4 ml) of the PRP were placed in the cuvette of a Payton platelet aggregometer.…”

“…Recently, endostatin was shown to be contained within platelets and released in response to thrombin (Ma et al, 2001). The platelet plays a key role in wound healing, including gastric ulcer healing (Ma et al, 2001), in part through the release of pro-and anti-angiogenic factors, endostatin being an example of the latter.…”