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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1227-1233.
Prepublished online as a Blood First Edition Paper on October 25, 2007; DOI 10.1182/blood-2007-09-113837.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet  granules and differentially released
Joseph E. Italiano, Jr1,2,
Jennifer L. Richardson1,
Sunita Patel-Hett1,2,
Elisabeth Battinelli1,3,
Alexander Zaslavsky2,
Sarah Short2,
Sandra Ryeom2,
Judah Folkman2, and
Giannoula L. Klement2,4
1 Translational Medicine Division, Brigham and Women's Hospital;
2 Vascular Biology Program, Department of Surgery, Children's Hospital;
3 Department of Hematology and Oncology, Beth Israel Deaconess Medical Center; and
4 Dana-Farber Cancer Institute, Boston, MA
Platelets, in addition to their function in hemostasis, play an important role in wound healing and tumor growth. Because platelets contain angiogenesis stimulators and inhibitors, the mechanisms by which platelets regulate angiogenesis remain unclear. As platelets adhere to activated endothelium, their action can enhance or inhibit local angiogenesis. We therefore suspected a higher organization of angiogenesis regulators in platelets. Using double immunofluorescence and immunoelectron microscopy, we show that pro- and antiangiogenic proteins are separated in distinct subpopulations of  -granules in platelets and megakaryocytes. Double immunofluorescence labeling of vascular endothelial growth factor (VEGF) (an angiogenesis stimulator) and endostatin (an angiogenesis inhibitor), or for thrombospondin-1 and basic fibroblast growth factor, confirms the segregation of stimulators and inhibitors into separate and distinct -granules. These observations motivated the hypothesis that distinct populations of -granules could undergo selective release. The treatment of human platelets with a selective PAR4 agonist (AYPGKF-NH2) resulted in release of endostatin-containing granules, but not VEGF-containing granules, whereas the selective PAR1 agonist (TFLLR-NH2) liberated VEGF, but not endostatin-containing granules. In conclusion, the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of -granules in megakaryocytes and platelets may provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis.
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