FoxC1-dependent regulation of vascular endothelial growth factor signaling in corneal avascularity

Angiogenesis is a crucial process whereby new blood vessels are formed from pre-existing vessels, and it occurs under both normal and pathophysiological conditions. The process is precisely regulated through the balance between proangiogenic and anti-angiogenic mechanisms, and many of these mechanisms have been well-characterized through extensive research. However, little is known about how angiogenesis is regulated at the transcriptional level. We have recently shown that deletion of the Forkhead box (Fox) transcription factor Foxc1 in cells of neural crest (NC) lineage leads to aberrant vessel growth in the normally avascular corneas of mice, and that the effect is cell type-specific because the corneas of mice lacking Foxc1 expression in vascular endothelial cells remained avascular. The NC-specific Foxc1 deletion was also associated with elevated levels of both proangiogenic factors, such as the matrix metalloproteases (MMPs) MMP-3, MMP-9, and MMP-19 and the angiogenic inhibitor soluble vascular endothelial growth factor receptor 1 (sVEGFR-1). Thus, FoxC1 appears to control angiogenesis by regulating two distinct and opposing mechanisms; if so, vascular development could be determined, at least in part, by a competitive balance between proangiogenic and anti-angiogenic FoxC1-regulated pathways. In this review, we describe the mechanisms by which FoxC1 regulates vessel growth and discuss how these observations could contribute to a more complete understanding of the role of FoxC1 in pathological angiogenesis.