It is here demonstrated that the set of gene expressions underlying the 
angiogenic balance in tissues can be molecularly reset en masse by a single 
protein. Using genome-wide expression profiling, coupled with RT-PCR and 
phosphorylation analysis, we show that the endogenous angiogenesis inhibitor 
endostatin downregulates many signaling pathways in human microvascular 
endothelium associated with proangiogenic activity. Simultaneously, endostatin 
is found to upregulate many antiangiogenic genes. The result is a unique 
alignment between the direction of gene regulation and angiogenic status. 
Profiling further reveals the regulation of genes not heretofore associated with 
angiogenesis. Our analysis of coregulated genes shows complex interpathway 
communications in an intricate signaling network that both recapitulates and 
extends on current understanding of the angiogenic process. More generally, 
insights into the nature of genetic networking from the cell biologic and 
therapeutic perspectives are revealed.