ESTROGEN, ANGIOGENESIS AND ENDOTHELIAL PROGENITOR CELLS

多条证据表明，雌激素(E)直接调节血管生成。在生理条件下，血管生成通常在子宫中观察到，与循环雌二醇(E2)和其他性类固醇水平的波动有关。在病理情况下，如乳腺癌，E、雌激素受体(ER)的表达、血管生成活性和肿瘤侵袭性之间存在明显的关联。尽管有这些一致的观察，但E在生理和病理情况下调节血管生成的机制尚未确定。先前的研究表明，造血干细胞(HSCs)和内皮祖细胞(EPC)起源于一种常见的前体细胞--血管母细胞。在这些研究的基础上，我们的实验室研究了来自外周血的干细胞分化为内皮细胞(EC)从而参与血管生成的可能性。额外的原始骨髓(BM)来源的EPC以及这些前体细胞在血管生成灶中的整合。因此，拟议的研究旨在澄清和扩展这些初步调查结果。这些研究旨在检验以下特定目标的假说：特定目的1：定义雌激素对EPC动力学的调控；特定目的2：确定雌激素受体在雌激素诱导的EPC介导的新生血管形成中的作用；特定目的3：研究介导雌激素诱导的EPC衍生的新生血管的某些机制。我们的初步数据表明，E2诱导的血管新生至少部分是BM来源的EPC募集和整合所致的血管生成的结果。这些数据与传统的血管生成范式(即来自预先存在的、完全分化的EC的萌芽)形成对比，后者被认为是E2诱导的血管形成的原因。E2诱导模型中新生血管的研究将提供机会在生理相关的背景下检查这些机制，从而辨别某些导致出生后新生血管的基本机制。

Multiple lines of evidence suggests that estrogen(E) directly modulates angiogenesis. Under physiologic conditions, angiogenesis is routinely observed in the uterus in association with fluctuations in the levels of circulating estradiol(E2) and other sex steroids. In pathologic circumstances, such as breast cancer, a clear association between E, estrogen receptor (ER) expression, angiogenic activity and tumor invasiveness has been drawn. Despite These consistent observations, the mechanisms by which E regulates angiogenesis under physiologic and pathologic circumstances have not been defined. Prior studies indicate that hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs) are derived from a common precursor, the hemangioblast. Based on these studies our laboratory investigated the possibilities that stem cells derived from peripheral blood could differentiation into endothelial cells (EC) and thereby participate in angiogenesis. Additional preliminary marrow (BM) derived EPC and the incorporation of these precursors into foci of vasculogenesis. Accordingly, the proposed studies are designed to clarify and extend these preliminary findings. These studies are organized to examine hypotheses the following specific aims: SPECIFIC AIM 1: Define Modulation of EPC kinetics y Estrogen; SPECIFIC AIM 2: Define the Role of Estrogen Receptor in Estrogen-induced, EPC-mediated Neovascularization; SPECIFIC AIM 3: Investigate Certain Mechanisms which Mediate Estrogen-Induced, EPC-Derived Neovascularization. Our preliminary data provide evidence that E2 induced neovascularization is the result, at least in part, of vasculogenesis resulting from recruitment and incorporation of BM derived EPC. These data are in contrast to the conventional paradigm of angiogenesis (i.e. sprouts derived from pre-existing, fully differentiated EC) which has been assumed to account for E2 induced blood vessel formation. The study of neovascularization in the model for E2 induction will provide the opportunity to examine these mechanisms in a physiologically relevant context and thereby discern certain fundamental mechanisms responsible for post-natal neovascularization.