VEGF-mediated inflammation precedes angiogenesis in adult brain.
Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis when infused continuously into adult rat brain tissue. In addition, VEGF has been shown to enhance permeability in brain vasculature. Adult rats were continuously infused with mouse VEGF into neocortex for up to 7 days. We studied the development of VEGF-induced vasculature in rat neocortex and evaluated the temporal expression of a wide variety of markers for inflammation and vascular leak in relation to the angiogenic response using immunohistochemistry and Western blot analysis. We report here that VEGF-mediated inflammation in brain is characterized by upregulation of ICAM-1 and the chemokine MIP-1alpha, as well as a preferential extravasation of monocytes. VEGF causes a dramatic breakdown of the blood-brain barrier, which is characterized by decreased investment of the vasculature with astroglial endfeet. Perivascular cells, in contrast, increase around the newly formed cerebrovasculature. In addition, breakdown of the blood-brain barrier, leukocyte extravasation, and extracellular matrix deposition occur before vascular proliferation. Furthermore, administration of low doses of VEGF induces permeability and inflammation without appreciable vascular proliferation.
Croll
Susan D
SD
Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. susan.croll@regeneron.com
Ransohoff
Richard M
RM
Cai
Ning
N
Zhang
Qing
Q
Martin
Francis J
FJ
Wei
Tao
T
Kasselman
Lora J
LJ
Kintner
Jennifer
J
Murphy
Andrew J
AJ
Yancopoulos
George D
GD
Wiegand
Stanley J
SJ
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018925:Chemokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004660:Encephalitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D019579:Neocortex / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology*
D018925:Chemokines; D018836:Inflammation Mediators; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1