title: A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing.
abstract: Angiogenesis alleviates hypoxic stress in ischemic tissues or during tumor progression. In addition to endothelial cell proliferation and migration, the angiogenic process requires bone marrow-derived cell (BMDC) recruitment to sites of neovascularization. However, the mechanism of communication between hypoxic tissues and the BM remains unknown. Using 2 models of hypoxia-induced angiogenesis (ischemic hindlimb surgery and subcutaneous tumor growth), we show that platelet infusion promotes BMDC mobilization into the circulation, BMDC recruitment into growing neovasculature, tumor vascularization, and blood flow restoration in ischemic limbs, whereas platelet depletion inhibits these effects. Thus, platelets are required for BMDC recruitment into ischemia-induced vasculature. Secretion of platelet α-granules, but neither dense granules nor platelet aggregation is crucial for BMDC homing and subsequent angiogenesis, as determined using VAMP-8(-/-), Pearl, and integrin Beta 3(-/-) platelets. Finally, platelets sequester tumor-derived promoters of angiogenesis and BMDC mobilization, which are counterbalanced by the antiangiogenic factor thrombospondin-1. A lack of thrombospondin-1 in platelets leads to an imbalance in proangiogenic and antiangiogenic factors and accelerates tumor growth and vascularization. Our data demonstrate that platelets stimulate BMDC homing in a VAMP-8-dependent manner, revealing a previously unknown role for platelets as key mediators between hypoxic tissues and the bone marrow during angiogenesis.
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH;
authors.forename: Weiyi
authors.initials: W
authors.lastname: Feng
authors.forename: Maria
authors.initials: M
authors.lastname: Madajka
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Kerr
authors.forename: Ganapati H
authors.initials: GH
authors.lastname: Mahabeleshwar
authors.forename: Sidney W
authors.initials: SW
authors.lastname: Whiteheart
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000502:physiology; D005260:Female; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D050683:R-SNARE Proteins / Q000235:genetics / Q000502:physiology; D055153:Stem Cell Niche / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D039661:Integrin beta3; D050683:R-SNARE Proteins; D019700:Thrombospondin 1; C491831:Vamp8 protein, mouse