title: Paradoxical effects of PDGF-BB overexpression in endothelial cells on engineered blood vessels in vivo.
abstract: Therapeutic revascularization with either exogenous angiogenic growth factors or vascular cells has yet to demonstrate efficacy in the clinic. Injection of angiogenic growth factors often produces unstable and abnormal blood vessels. Blood vascular networks derived from implanted endothelial cells persist only transiently due to the insufficient recruitment of perivascular cells. We hypothesize that a combination of the two approaches may act synergistically to yield a better result. To enhance the recruitment of perivascular cells, human umbilical vein endothelial cells were genetically modified to overexpress platelet-derived growth factor (PDGF)-BB. PDGF-BB overexpression promoted both proliferation and migration of perivascular precursor cells (10T1/2 cells) in vitro. When mock-infected endothelial cells were implanted alone in vivo, they formed transient blood vascular networks that regressed by day 30. PDGF-BB overexpression enhanced the survival of endothelial cells in vivo. However, the PDGF-BB-expressing vessel network failed to establish patent blood flow. Co-implantation of PDGF-BB-overexpressing endothelial cells with 10T1/2 cells paradoxically resulted in the rapid regression of the vascular networks in vivo. PDGF-BB stimulated the expression of both chemokine (C-C motif) ligand 2 (CCL2) and CCL7 in 10T1/2 cells and led to the increased accumulation of macrophages in vivo. These results suggest a potential negative interaction between angiogenic growth factors and vascular cells; their use in combination should be carefully tested in vivo for such opposing effects.
authors.affiliation: Department of RadiationOncology, Edwin L Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Au
authors.forename: Joshua
authors.initials: J
authors.lastname: Tam
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Lin
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054410:Chemokine CCL7 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023822:Tissue Engineering / Q000379:methods*; D014161:Transduction, Genetic; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D018932:Chemokine CCL2; D054410:Chemokine CCL7; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin