Abstract
Proteinase-activated receptors (PARs) are expressed on the surface of many cells, but those on the platelet have been among the most thoroughly characterized. PARs act as key receptors mediating the proaggregatory and prosecretory effects of thrombin. In addition to contributing to hemostasis, platelets are increasingly being viewed as important contributors to healing and to tumor growth. This is attributable to the many pro- and anti-angiogenic factors that are stored within platelets, which can be released at the sites of injury and new vessel growth. In this paper, we review the importance of the platelet in gastric ulcer healing, the contribution of platelet-contained angiogenic factors to the healing of gastric ulcers, and the role of PARs in regulating the release of angiogenic factors from platelets. Taken together, our results suggest that PARs, including those expressed on platelets, are a rational therapeutic target for modulating healing processes and tumor growth.
Similar content being viewed by others
References
Mehta P: Potential role of platelets in the pathogenesis of tumor metastasis. Blood 63:55–63, 1984
Gasic GJ: Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metastasis Rev 3:99–114, 1984
Nash GF, Walsh DC, Kakkar AK: The role of the coagulation system in tumor angiogenesis. Lancet Oncol 2:608–613, 2001
Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL: Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci USA 98:6470–6475, 2001
Ma L, del Soldato P, Wallace JL: Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: shifting the angiogenic balance. Proc Natl Acad Sci USA 99:13243–13247, 2002
Ma L, Perini R, Klein A, McKnight W, Dicay M, Hollenberg MD, Wallace JL: Proteinase-activated receptors (PAR)-1 and -4 counter-regulate endostatin and VEGF release from human platelets. Proc Natl Acad Sci USA 102:216–220, 2005
Dhanabal M, Ramchandran R, Volk R, Stillman IE, Lombardo M, Iruela-Arispe ML, Simons M, Sukhatme VP: Endostatin: yeast production, mutants, and antitumor effect in renal cell carcinoma. Cancer Res 59:189–197, 1999a
Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP: Endostatin induces endothelial cell apoptosis. J Biol Chem 274:11721–11726, 1999b
Distler O, Neidhart M, Gay RE, Gay S: The molecular control of angiogenesis. Int Rev Immunol 21:33–49, 2002
Maloney JP, Silliman CC, Ambruso DR, Wang J, Tuder RM, Voelkel NF: In vitro release of vascular endothelial growth factor during platelet aggregation. Am J Physiol 275:H1054–H1061, 1998
Miyazono K, Heldin CH: High-yield purification of platelet-derived endothelial cell growth factor: structural characterization and establishment of a specific antiserum. Biochemistry 28:1704–1710, 1989
Hwang DL, Lev-Ran A, Yen CF, Sniecinski I: Release of different fractions of epidermal growth factor from human platelets in vitro: preferential release of 140 kDa fraction. Regul Pept 37:95–100, 1992
Linder BL, Chernoff A, Kaplan KL, Goodman DS: Release of platelet-derived growth factor from human platelets by arachidonic acid. Proc Natl Acad Sci USA 76:4107–4111, 1979
Pipili-Synetos E, Papadimitriou E, Maragoudakis ME: Evidence that platelets promote tube formation by endothelial cells on matrigel. Br J Pharmacol 125:1252–1257, 1998
Konturek SJ, Brzozowski T, Majka J, Pytko-Polonczyk J, Stachura J: Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharmacol 239:215–217, 1993
Elliott SN, McKnight W, Cirino G, Wallace JL: A nitric oxide-releasing nonsteroidal antiinflammatory drug accelerates gastric ulcer healing in the rat. Gastroenterology 109:524–530, 1995
Vergnolle N, Wallace JL, Bunnett NW, Hollenberg MD: Protease-activated receptors in inflammation, neuronal signaling, and pain. Trends Pharmacol Sci 22:146–152, 2001
Uehara A, Muramoto K, Takada H, Sugawara S: Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2. J Immunol 170:5690–5696, 2003
Sambrano GR, Huang W, Faruqi T, Mahrus S, Craik C, Coughlin SR: Cathepsin G activates protease-activated receptor-4 in human platelets. J Biol Chem 275:6819–6823, 2000
Vu TK, Hung DT, Wheaton VI, Coughlin SR: Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057–1068, 1991
Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR: Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 103:879–887, 1999
Coughlin SR: Thrombin signalling and protease-activated receptors. Nature 407:258–264, 2000
Ruef J, Kacharava A, Pohl J, Bode C, Runge MS: Indications for the presence of an atypical protease-activated receptor on rat platelets. Ann Hematol 79:604–611, 2000
Ma L, Hollenberg MD, Wallace JL: Thrombin-induced platelet endostatin release is blocked by a proteinase activated receptor-4 (PAR4) antagonist. Br J Pharmacol 134:701–704, 2001
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Perini, R., Wallace, J.L. Roles of Platelets and Proteinase-Activated Receptors in Gastric Ulcer Healing. Dig Dis Sci 50 (Suppl 1), S12–S15 (2005). https://doi.org/10.1007/s10620-005-2801-8
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10620-005-2801-8