Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF165b
Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF165b
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DOI：
10.1096/fj.07-9718com
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Harper, Steven J.
中科院分区：
文献类型：
--
作者：
Qiu, Yan;Bevan, Heather;Harper, Steven J.
怀孕期间乳腺组织发生广泛的组织重塑，导致乳腺的生长和发育，并伴有广泛的血管重塑，这被认为依赖于血管内皮生长因子（VEGF）。我们在此表明，VEGF 的内源性抗血管生成剪接亚型 VEGF(165)b 通常在非哺乳期人和小鼠乳腺中表达，并且在哺乳期间在 WT 小鼠中下调。为了证明 VEGF165b 在乳腺组织中的生理作用，我们在小鼠乳腺肿瘤病毒 (MMTV) 增强子/启动子的控制下产生了表达 VEGF165b 的转基因 (TG) 小鼠。这些小鼠在乳腺发育过程中增加了乳腺组织中 VEGF165b 的表达。 TG 母亲（而非 TG 父亲）的后代在出生后不久就会死亡。雌性TG小鼠的血管较少，乳腺组织中的血液较少，脂肪垫的肺泡覆盖受损，并且不能产生足够的乳汁来滋养幼仔。这些发现表明，乳腺中 VEGF165b 的内源性过度表达会抑制生理性血管生成，并且 VEGF 亚型平衡的调节是乳腺泡发育和产奶的必要条件。这项研究为内源性抗血管生成 VEGF 亚型在正常生理学中的作用提供了第一个证据——它们的下调是有效产奶所必需的。
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 antiangiogenic 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 VEGF165b in mammary tissue, we generated transgenic (TG) mice expressing VEGF165b, under the control of the mouse mammary tumor virus (MMTV) enhancer/promoter. These mice increase expression of VEGF165b in mammary 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 VEGF165b 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.