Inhibition of Vascular Endothelial Growth Factor Receptor Signal Transduction Blocks Follicle Progression but Does Not Necessarily Disrupt Vascular Development in Perinatal Rat Ovaries1
Inhibition of Vascular Endothelial Growth Factor Receptor Signal Transduction Blocks Follicle Progression but Does Not Necessarily Disrupt Vascular Development in Perinatal Rat Ovaries1
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抑制血管内皮生长因子受体信号转导可阻止卵泡进展，但不一定会破坏围产期大鼠卵巢的血管发育1
作者：
R. McFee;R. Artac;Ryann M. McFee;D. Clopton;Robyn Smith;T. Rozell;A. Cupp
我们假设血管内皮生长因子A(VEGFA)血管生成异构体及其受体Flt1和KDR调节围产期大鼠卵巢的卵泡发育。每个VEGFA血管生成异构体都有独特的功能(基于其外显子)，影响大血管的扩散性、细胞迁移、分支和发育。在发育中的大鼠卵巢中检测到了VEGFA120、VEGFA164和VEGFA188三种血管生成异构体，定量RT-PCR结果显示，VEGFA120和VEGFA164mRNA在出生后表达较丰富，而VEGFA188mRNA在胚胎第16天表达最高。VEGFA及其受体定位于各卵泡发育阶段的颗粒前和颗粒细胞以及晚期卵泡膜细胞。为探讨VEGFA在卵巢发育中的作用，在出生后第3/4天的大鼠卵巢中加入8μM VEGFR-TKI(一种阻断Flt1和KDR的酪氨酸激酶抑制剂)。与对照组相比，注射VEGFR-TKI组的卵巢血管发育减少94%(P<；0.0001)，原始卵泡(0期)增多，早期初级、过渡性和次级卵泡(分别为1、3和4期)减少，卵泡总数增加(P<；0.005)。KDR特异性抑制剂V1被用来确定仅抑制KDR的效果。30μM V1处理对卵巢血管密度无明显影响，但早期初级卵泡、过渡性卵泡和次级卵泡较少，初级卵泡(第2期)较多(P<；0.05)。我们的结论是，VEGFA可能参与原始卵泡的激活和卵泡的成熟和存活，这些都是通过血管依赖和血管非依赖的机制来调节的。
We hypothesized that vascular endothelial growth factor A (VEGFA) angiogenic isoforms and their receptors, FLT1 and KDR, regulate follicular progression in the perinatal rat ovary. Each VEGFA angiogenic isoform has unique functions (based on its exons) that affect diffusibility, cell migration, branching, and development of large vessels. The Vegfa angiogenic isoforms (Vegfa_120, Vegfa_164, and Vegfa_188) were detected in developing rat ovaries, and quantitative RT-PCR determined that Vegfa_120 and Vegfa_164 mRNA was more abundant after birth, while Vegfa_188 mRNA was highest at Embryonic Day 16. VEGFA and its receptors were localized to pregranulosa and granulosa cells of all follicle stages and to theca cells of advanced-stage follicles. To determine the role of VEGFA in developing ovaries, Postnatal Day 3/4 rat ovaries were cultured with 8 μM VEGFR-TKI, a tyrosine kinase inhibitor that blocks FLT1 and KDR. Ovaries treated with VEGFR-TKI had vascular development reduced by 94% (P < 0.0001), with more primordial follicles (stage 0), fewer early primary, transitional, and secondary follicles (stages 1, 3, and 4, respectively), and greater total follicle numbers compared with control ovaries (P < 0.005). V1, an inhibitor specific for KDR, was utilized to determine the effects of only KDR inhibition. Treatment with 30 μM V1 had no effect on vascular density; however, treated ovaries had fewer early primary, transitional, and secondary follicles and more primary follicles (stage 2) compared with control ovaries (P < 0.05). We conclude that VEGFA may be involved in primordial follicle activation and in follicle maturation and survival, which are regulated through vascular-dependent and vascular-independent mechanisms.
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DOI：
10.1073/pnas.97.18.10242
发表时间：
2000-08-29
影响因子：
11.1
作者：
Jin, KL;Mao, XO;Greenberg, DA
通讯作者：
Greenberg, DA
影响因子：
3.6
作者：
HIRSHFIELD, AN
通讯作者：
HIRSHFIELD, AN
影响因子：
4.8
作者：
G. Dissen;Carmen Romero;A. Hirshfield;S. Ojeda
通讯作者：
G. Dissen;Carmen Romero;A. Hirshfield;S. Ojeda
影响因子：
3.1
作者：
R. Zimmermann;T. Hartman;Peter Bohlen;M. Sauer;Jan Kitajewski
通讯作者：
R. Zimmermann;T. Hartman;Peter Bohlen;M. Sauer;Jan Kitajewski
DOI：
10.1002/tera.1420340105
发表时间：
1986-08-01
期刊：
TERATOLOGY
影响因子：
--
作者：
IGUCHI, T;TAKASUGI, N;MILLS, KT
通讯作者：
MILLS, KT