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Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF 165 b
Author(s) -
Qiu Yan,
Bevan Heather,
Weeraperuma Sudath,
Wratting Daniel,
Murphy David,
Neal Christopher R.,
Bates David O.,
Harper Steven J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9718com
Subject(s) - mammary gland , lactation , angiogenesis , endogeny , endocrinology , medicine , vascular endothelial growth factor , biology , gene isoform , genetically modified mouse , mammary tumor , transgene , vegf receptors , breast cancer , cancer , pregnancy , gene , biochemistry , genetics
Extensive tissue remodeling occurs in breast tissue during pregnancy, resulting in growth and development of the mammary gland associated with extensive vascular remodeling, which is thought to be dependent on vascular endothelial growth factor (VEGF). We show here that the endogenous antiangio‐genic splice isoform of VEGF, VEGF 165 b, is normally expressed in nonlactating human and mouse breast, and is down‐regulated in WT mice during lactation. To demonstrate the physiological role of VEGF 165 b in mammary tissue, we generated transgenic (TG) mice expressing VEGF 165 b, under the control of the mouse mammary tumor virus (MMTV) enhancer/promoter. These mice increase expression of VEGF 165 b in mam‐mary tissue during mammary development. The offspring of TG mothers, but not TG fathers, die shortly after birth. The female TG mice have fewer blood vessels, less blood in the mammary tissue, and impaired alveolar coverage of the fat pad, and do not produce sufficient milk for nourishment of their pups. These findings demonstrate that endogenous overexpression of VEGF 165 b in the mammary gland inhibits physiological angiogenesis and that the regulation of the balance of VEGF isoforms is a requirement for mammary alveolar development and milk production. This study provides the first evidence for the role of endogenous antiangiogenic VEGF isoforms in normal physiology— their down‐regulation is required for effective milk production. Qiu Y., Bevan, H., Weeraperuma, S., Wratting, D., Murphy, D., Neal, C. R., Bates, D. O., Harper S. J. Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF 165 b. FASEB J. 22, 1104–1112 (2008)