VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment.
Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1(+) lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A(164/164) or VEGF-A(188/188) (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A-mediated lymphangiogenesis. Either systemic depletion of all bone marrow-derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.
Cursiefen
Claus
C
The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA. cursiefen@vision.eri.harvard.edu
Chen
Lu
L
Borges
Leonardo P
LP
Jackson
David
D
Cao
Jingtai
J
Radziejewski
Czeslaw
C
D'Amore
Patricia A
PA
Dana
M Reza
MR
Wiegand
Stanley J
SJ
Streilein
J Wayne
JW
D000818:Animals; D016510:Corneal Neovascularization / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A