title: Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization.
abstract: Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch. TSPs inhibited thrombopoiesis, diminished bone marrow microvascular reconstruction following myelosuppression, and limited the extent of revascularization in a model of hind limb ischemia. We demonstrate that thrombopoietic recovery following myelosuppression was significantly enhanced in mice deficient in both TSP1 and TSP2 (TSP-DKO mice) in comparison with WT mice. Megakaryocyte and platelet levels in TSP-DKO mice were rapidly restored, thereby accelerating revascularization of myelosuppressed bone marrow and ischemic hind limbs. In addition, thrombopoietic cells derived from TSP-DKO mice were more effective in supporting neoangiogenesis in Matrigel plugs. The proangiogenic activity of TSP-DKO thrombopoietic cells was mediated through activation of MMP-9 and enhanced release of stromal cell-derived factor 1. Thus, TSP-deficient thrombopoietic cells function as proangiogenic agents, accelerating hemangiogenesis within the marrow and revascularization of ischemic hind limbs. As such, interference with the release of cellular stores of TSPs may be clinically effective in augmenting neoangiogenesis.
authors.affiliation: Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kopp
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: M Johan
authors.initials: MJ
authors.lastname: Broekman
authors.forename: Scott T
authors.initials: ST
authors.lastname: Avecilla
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petit
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Ramos
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Tabitha
authors.initials: T
authors.lastname: Kopp
authors.forename: Paul
authors.initials: P
authors.lastname: Bornstein
authors.forename: David K
authors.initials: DK
authors.lastname: Jin
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Marcus
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology; D001853:Bone Marrow / Q000098:blood supply* / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D008533:Megakaryocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D013267:Stilbenes / Q000378:metabolism; D034061:Thrombopoiesis / Q000502:physiology; D013926:Thrombopoietin / Q000235:genetics / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D000099262:Thrombospondin 2
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D013267:Stilbenes; D013926:Thrombopoietin; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2; C515256:Cxcl12 protein, mouse; C058728:fosbretabulin