ESTROGEN, ANGIOGENESIS AND ENDOTHELIAL PROGENITOR CELLS

多种证据表明雌激素(E)直接调节血管生成。在生理条件下，子宫血管生成通常与循环雌二醇（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）表达，血管生成活性和肿瘤侵袭性之间的明确关联已经被绘制出来。尽管有这些一致的观察结果，但在生理和病理情况下，E调节血管生成的机制尚未明确。先前的研究表明，造血干细胞（hsc）和内皮祖细胞（EPCs）来源于一个共同的前体，即成血管细胞。基于这些研究，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）并参与血管生成的可能性。额外的初步骨髓（BM）衍生EPC和这些前体纳入血管发生灶。因此，拟议的研究旨在澄清和扩大这些初步调查结果。这些研究被组织起来以检验以下假设：具体目标1：定义雌激素对EPC动力学的调节；特异性目标2：明确雌激素受体在雌激素诱导、内皮祖细胞介导的新生血管中的作用；特定目的3：研究雌激素诱导的内皮细胞衍生的新生血管形成的某些机制。我们的初步数据提供了E2诱导的新生血管形成的证据，至少在一定程度上是由BM衍生的EPC的募集和合并引起的血管生成的结果。这些数据与传统的血管生成模式（即由预先存在的、完全分化的EC产生的芽）形成对比，后者被认为是E2诱导血管形成的原因。E2诱导模型中新生血管的研究将提供在生理学相关背景下检查这些机制的机会，从而辨别出负责产后新生血管的某些基本机制。

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.