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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.
 Previous Article | Next Article 
Submitted September 20, 2007
Accepted October 16, 2007
Angiogenesis is regulated by a novel mechanism: Pro- and anti-angiogenic proteins are organized into separate platelet  -granules and differentialy released
Joseph E. Italiano Jr*, Jennifer L. Richardson, Sunita Patel-Hett, Elisabeth Battinelli, Alexander Zaslavsky, Sarah Short, Sandra Ryeom, Judah Folkman, and Giannoula L Klement
Translational Medicine Division, Brigham and Women's Hospital, Boston, MA, United States
Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, MA, United States
Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, MA, United States
Dana-Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: jitaliano{at}rics.bwh.harvard.edu.
Platelets, in addition to their function in hemostasis, play an important role in wound healing and tumor growth. Because platelets contain both 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 both platelets and megakaryocytes. Double immunofluorescence labeling of VEGF (an angiogenesis stimulator) and endostatin (an angiogenesis inhibitor), or for thrombospondin-1 and basic FGF, 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 PAR-4 agonist (AYPGKF-NH2) resulted in release of endostatin-containing granules, but not VEGF-containing granules, while the selective PAR-1 agonist (TFLLR-NH2) liberated VEGF, but not endostatin-containing granules. We conclude that the separate packaging of angiogenesis regulators into pharmacologically and morphologically distinct populations of -granules in megakaryocytes and platelets may be provide a mechanism by which platelets can locally stimulate or inhibit angiogenesis.
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