Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury.
BACKGROUND
The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury.


RESULTS
Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (P<0.05), resulting in decreased neointima formation at 4 weeks compared with control (P<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (P<0.01) and increased neointima formation at 4 weeks (P<0.01).


CONCLUSIONS
VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.
Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Randolph
R
Hutter
Francine E
FE
Carrick
Carolina
C
Valdiviezo
Claire
C
Wolinsky
John S
JS
Rudge
Stanley J
SJ
Wiegand
Valentin
V
Fuster
Juan J
JJ
Badimon
Bernhard V
BV
Sauter
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D002455:Cell Division; D042783:Endothelial Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000293:injuries* / Q000473:pathology; D015316:Genetic Therapy; D006801:Humans; D006965:Hyperplasia; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D016037:Single-Blind Method; D017539:Tunica Intima / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
D011993:Recombinant Fusion Proteins; C475927:VEGF-Trap fusion protein, recombinant; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor