Hervé M A J, Meduri G, Petit F G, Domet T S, Lazennec G, Mourah S, Perrot-Applanat M
INSERM U553, Institut Universitaire d'Hématologie, Hôpital Saint-Louis/Bâtiment INSERM, 1 avenue Claude Vellefaux, 75010 Paris, France.
J Endocrinol. 2006 Jan;188(1):91-9. doi: 10.1677/joe.1.06184.
The induction of vascular endothelial growth factor (VEGF) expression by 17beta-estradiol (E(2)) in many target cells, including epithelial cells, fibroblasts and smooth muscle cells, suggests a role for this hormone in the modulation of angiogenesis and vascular permeability. We have already described a cyclic increase in Flk-1/KDR-expressing capillaries in the human endometrium during the proliferative and mid-secretory phases, strongly suggestive of an E(2) effect on Flk-1/KDR expression in the endometrial capillaries. However, it is unclear whether these processes are due to a direct effect of E(2) on endothelial cells. Using immunohistochemistry, we report an increase in Flk-1/KDR expression in endometrial capillaries of ovariectomized mice treated with E(2), or both E(2) and progesterone. This process is mediated through estrogen receptor (ER) activation. In vitro experiments using quantitative RT-PCR analysis demonstrate that Flk-1/KDR expression was not regulated by E(2) in human endothelial cells from the microcirculation (HMEC-1) or macrocirculation (HUVEC), even in endothelial cells overexpressing ERalpha or ERbeta after ER-mediated adenovirus infection. In contrast, Flk-1/KDR expression was up-regulated by VEGF itself, in a time- and dose-dependent manner, with the maximal response at 10 ng/ml. Thus, we suggest that E(2) up-regulates Flk-1/KDR expression in vivo in endothelial cells mainly through the modulation of VEGF by a paracrine mechanism. It is currently unknown whether or not the endothelial origin might account for differences in the E(2)-modulation of VEGF receptor expression, particularly in relation to the vascular bed of sex steroid-responsive tissues.
17β-雌二醇（E₂）在包括上皮细胞、成纤维细胞和平滑肌细胞在内的许多靶细胞中诱导血管内皮生长因子（VEGF）表达，提示该激素在调节血管生成和血管通透性方面发挥作用。我们已经描述过，在增殖期和分泌中期，人子宫内膜中表达Flk-1/KDR的毛细血管呈周期性增加，这强烈提示E₂对子宫内膜毛细血管中Flk-1/KDR表达有影响。然而，尚不清楚这些过程是否是由于E₂对内皮细胞的直接作用。通过免疫组织化学，我们报道在用E₂或E₂与孕酮联合处理的去卵巢小鼠的子宫内膜毛细血管中，Flk-1/KDR表达增加。这个过程是通过雌激素受体（ER）激活介导的。使用定量RT-PCR分析的体外实验表明，即使在内皮细胞经ER介导的腺病毒感染后过表达ERα或ERβ的情况下，E₂也不会调节来自微循环（HMEC-1）或大循环（HUVEC）的人内皮细胞中的Flk-1/KDR表达。相反，VEGF本身以时间和剂量依赖性方式上调Flk-1/KDR表达，在10 ng/ml时达到最大反应。因此，我们认为E₂在体内主要通过旁分泌机制调节VEGF来上调内皮细胞中Flk-1/KDR的表达。目前尚不清楚内皮细胞起源是否可能解释E₂对VEGF受体表达调节的差异，特别是与性类固醇反应性组织的血管床相关的差异。
