The Role and Function of the Vegf Pathway during Palate Development

Abstract

Objectives:

(1) Define the evolution of palatal vascularization during palatal shelf formation and effects of vascular endothelial growth factor (Vegf) deletion in the cranial neural crest. (2) Determine downstream mediators of Vegf signaling.

Methods:

Conditional deletion of Vegf using Wnt1-Cre; Vegf F/F mice (VegfCKO) led to a cleft palate phenotype. PECAM staining was used to determine vascular patterning in the VegfCKO developing palate daily from E13.5 to E16.5 compared to controls. The VegfCKO palate shelves at E13.5 and E14.5 were analyzed using quantitative PCR (qPCR) to assess mediators and targets of Vegf signaling.

Results:

VegfCKO had aberrant vascular branching via PECAM staining in comparison to controls. In E13.5 VegfCKO mice, there were no significant differences in mediators and targets of VEGF signaling measured by qPCR. However, at E14.5, VegfCKO palates demonstrated significant reductions in pyruvate dehydrogenase kinase (PDK4) (P = .045), which is a glycolytic gene, and stromal cell-derived factor 1 (SDF1) (P = .036), which induces endothelial migration.

Conclusions:

Vegf was required for palatal vascularization and palatal elongation. During palatal development Vegf was upstream of SDF1, a cytokine necessary for endothelial progenitor cell recruitment and migration. Vegf also modulates glycolysis through variations in PDK4, a protein involved in glucose metabolism.