Angiogenic inhibition reduces germinal matrix hemorrhage.
The germinal matrix of premature infants is selectively vulnerable to hemorrhage within the first 48 h of life. To assess the role of vascular immaturity in germinal matrix hemorrhage (GMH), we evaluated germinal matrix angiogenesis in human fetuses and premature infants, as well as in premature rabbit pups, and noted active vessel remodeling in all three. Vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial cell proliferation were present at consistently higher levels in the germinal matrix relative to the white matter anlagen and cortical mantle. On that basis, we asked whether prenatal treatment with either of two angiogenic inhibitors, the COX-2 inhibitor celecoxib, or the VEGFR2 inhibitor ZD6474, could suppress the incidence of GMH in premature rabbit pups. Celecoxib treatment decreased angiopoietin-2 and VEGF levels as well as germinal matrix endothelial proliferation. Furthermore, treatment with celecoxib or ZD6474 substantially decreased the incidence of GMH. Thus, by suppressing germinal matrix angiogenesis, prenatal celecoxib or ZD6474 treatment may be able to reduce both the incidence and severity of GMH in susceptible premature infants.
Ballabh
Praveen
P
Department of Pediatrics, New York Medical College-Westchester Medical Center, Valhalla, New York 10595, USA. pballabh@msn.com
Xu
Hongmin
H
Hu
Furong
F
Braun
Alex
A
Smith
Kira
K
Rivera
Aracelie
A
Lou
Nanhong
N
Ungvari
Zoltan
Z
Goldman
Steven A
SA
Csiszar
Anna
A
Nedergaard
Maiken
M
D037881:Aborted Fetus; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007234:Infant, Premature; D020300:Intracranial Hemorrhages / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D042702:Angiopoietin-2; D052246:Cyclooxygenase 2 Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D040301:Vascular Endothelial Growth Factor Receptor-2; D000068579:Celecoxib; C452423:vandetanib