Regulation and localization of vascular endothelial growth factor within the mammary glands during the transition from late gestation to lactation

Abstract

The vascular network within the developing mammary gland (MG) grows in concert with the epithelium to prepare for lactation, although the mechanisms coordinating this vascular development are unresolved. Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and vascular permeability in the MG during pregnancy and lactation, where its expression is upregulated by prolactin. Given our previous finding that late-gestational hyperprolactinemia induced by domperidone (DOM) increased subsequent milk yield from gilts, we sought to establish changes in vascular development during late gestation and lactation in the MGs of these pigs and determine whether DOM altered MG angiogenesis and the factors regulating it. Gilts received either no treatment (n = 6) or DOM (n = 6) during late gestation, then had their MG biopsied from late gestation through lactation to assess microvessel density, VEGF-A distribution and messenger RNA expression, and aquaporin (AQP) gene expression. Microvessel density in the MG was unchanged during gestation then increased between days 2 and 21 of lactation (P < 0.05). The local expression of messenger RNA for VEGF-A120, VEGF-A147, VEGF-A164, VEGF-A164b, VEGF-A188, VEGF receptors-1 and -2, and AQP1 and AQP3 all generally increased during the transition from gestation to lactation (P < 0.05). Immunostaining localized VEGF-A to the apical cytoplasm of secretory epithelial cells, consistent with a far greater concentration of VEGF-A in colostrum and/or milk vs plasma (P < 0.0001). There was no effect of DOM on any of the variables analyzed. In summary, we found that vascular development in the MG increases during lactation in first-parity gilts and that VEGF-A is a part of the mammary secretome. Although late-gestational hyperprolactinemia increases milk yield, there was no evidence that it altered vascular development.

Transcriptional changes in the mammary gland during lactation revealed by single cell sequencing of cells from human milk

“…2b-c, Supplementary Table 1, 3 ). Other genes found to be among the top significantly upregulated in LC1 were vascular endothelial growth factor A ( VEGFA ) found to promote vascularization of the mammary gland during lactation 21 and long non-coding RNA NEAT1 , found to be essential for lactation 22 (Fig. 2b-c, Supplementary Table 1, 3 ).…”

Hypoalbuminemia: Pathogenesis and Clinical Significance

“…An essential element consists of growth factor–induced (eg, VEGF) increases in vascular permeability. VEGF expression and increased vascular permeability occur in infection, trauma, during fetal and postnatal growth, preparing for lactation, cancer, protein‐losing enteropathy, and nephrotic syndrome (Table ). The positive role of VEGF and its effect on angiogenesis and vascular permeability is supported by the evidence that treatment with anti‐VEGF in renal cancer aggravates renal failure …”

Hyperprolactinaemia – a problem in patients from the reproductive period to the menopause

“…There are many substances that raise the concentration of prolactin. They include: a vasoactive intestinal peptide, dopamine, serotonin [3], epithelial growth factor, oxytocin, oestrogens, and histidine [8]. Blood PRL concentrations are also influenced by the hormones of the thyroid gland.…”