title: Proangiogenic Properties of Thrombospondin-4.
abstract: OBJECTIVE
  Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis.
  
  
  RESULTS
  The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using Thbs4(-/-) mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in Thbs4(-/-) mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from Thbs4(-/-) mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin α2 and gabapentin receptor α2δ-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4.
  
  
  CONCLUSIONS
  TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Santoshi
authors.initials: S
authors.lastname: Muppala
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Ella
authors.initials: E
authors.lastname: Frolova
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Roy
authors.initials: R
authors.lastname: Xiao
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Irene
authors.initials: I
authors.lastname: Krukovets
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Suzy
authors.initials: S
authors.lastname: Yoon
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: George
authors.initials: G
authors.lastname: Hoppe
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.).
authors.forename: Edward
authors.initials: E
authors.lastname: Plow
authors.affiliation: From the Department of Molecular Cardiology (S.M., E.F., R.X., I.K., E.P., O.S.-A.), and Cole Eye Institute (S.Y., G.H.), Cleveland Clinic, OH; and ImageIQ Inc, Cleveland, OH (A.V.). stenino@ccf.org.
authors.forename: Olga
authors.initials: O
authors.lastname: Stenina-Adognravi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019699:Thrombospondins; C101864:thrombospondin 4; D004247:DNA
keywords: angiogenesis; extracellular matrix; thrombospondin-4