Viral serpin, Serp-1, inhibits endogenous angiogenesis in the chicken chorioallantoic membrane model.
BACKGROUND
Angiogenesis is a critical factor in the development of malignant tumors, in arthritic joints, and in cardiovascular disease. In cardiovascular disease, angiogenesis is recognised both as a potential therapy and as a complicating factor in atherosclerotic plaque rupture and thrombotic obstruction. Serine proteases regulate thrombosis, inflammation, and cell invasion, events that trigger various stages of angiogenesis and are in turn regulated by inhibitors, termed serpins. Serp-1 is a secreted anti-inflammatory viral serpin that profoundly inhibits early mononuclear cell invasion, and the development of atherosclerosis, transplant vasculopathy, and arthritis in a range of animal models.


METHODS
The capacity of Serp-1 to alter angiogenesis was evaluated in the chicken chorioallantoic membrane (CAM) model using morphometric analysis of vascular changes and RT-PCR to explore alterations in gene expression.


RESULTS
Serp-1 inhibited endogenous angiogenesis in a dose-dependent manner, with associated altered expression of laminin and vascular endothelial growth factor (VEGF). Serp-1 was ineffective in CAMs no longer in the rapid growth phase. Similar inhibition of angiogenesis was detected after inhibition of VEGF, but not after treatment with the inactivated reactive center loop mutant of Serp-1.


CONCLUSIONS
The angiogenic process can be controlled using Serp-1, an anti-inflammatory agent that is effective at low concentrations with rapid reversibility, targets endothelial cells, and reduces the availability of VEGF. These properties may be especially important in cardiovascular disease, reducing plaque destabilization. It is likely that the anti-angiogenic activity of Serp-1 contributes to the observed anti-inflammatory and anti-atherogenic actions with potential importance in this therapeutic setting.
Richardson
Mary
M
Juravinski Cancer Centre, Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Liu
Liying
L
Dunphy
Lauren
L
Wong
David
D
Sun
Yunming
Y
Viswanathan
Kasinath
K
Singh
Gurmit
G
Lucas
Alexandra
A
D000818:Animals; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply* / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D007797:Laminin / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects; D014764:Viral Proteins / Q000494:pharmacology*
D007797:Laminin; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins