Regulation of VEGF and VEGF receptor expression in the rodent mammary gland during pregnancy, lactation, and involution.

Vascular endothelial growth factors (VEGFs) are endothelial cell-specific mitogens with potent angiogenic and vascular permeability-inducing properties. VEGF, VEGF-C, and VEGFRs -1, -2, and -3 were found to be expressed in post-pubertal (virgin) rodent mammary glands. VEGF was increased during pregnancy (5-fold) and lactation (15-19-fold). VEGF-C was moderately increased during pregnancy and lactation (2- and 3-fold respectively). VEGF levels were reduced by approximately 75% in cleared mouse mammary glands devoid of epithelial components, demonstrating that although the epithelial component is the major source of VEGF, approximately 25% is derived from stroma. This was confirmed by the findings (a) that VEGF transcripts were expressed predominantly in ductal and alveolar epithelial cells, and (b) that VEGF protein was localized to ductal epithelial cells as well as to the stromal compartment including vascular structures. VEGF was detected in human milk. Finally, transcripts for VEGFRs -2 and -3 were increased 2-3-fold during pregnancy, VEGFRs -1, -2 and -3 were increased 2-4-fold during lactation, and VEGFRs -2 and -3 were decreased by 20-50% during involution. These results point to a causal role for the VEGF ligand-receptor pairs in pregnancy-associated angiogenesis in the mammary gland, and suggest that they may also regulate vascular permeability during lactation.