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，在子宫中经常观察到血管生成，并与循环雌二醇（E2）和其他性类固醇水平的波动相关。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的明确关联已经得出。尽管有这些一致的观察结果，在生理和病理情况下E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（HSC）和内皮祖细胞（EPCs）来源于一个共同的前体，成血管细胞。在此基础上，本实验室研究了外周血干细胞向内皮细胞分化并参与血管生成的可能性。额外的初步骨髓（BM）来源的EPC和这些前体的合并到血管发生的病灶。因此，拟议的研究旨在澄清和扩展这些初步调查结果。组织这些研究以检查以下特定目的的假设：特定目的1：确定雌激素对EPC动力学的调节;特定目的2：确定雌激素受体在雌激素诱导的EPC介导的新血管形成中的作用;特定目的3：调查介导雌激素诱导的EPC衍生的新血管形成的某些机制。我们的初步数据提供的证据表明，E2诱导的新血管形成的结果，至少部分，从骨髓来源的EPC的招聘和纳入导致的血管发生。这些数据与传统的血管生成范例（即，源自预先存在的、完全分化的EC的芽）形成对比，传统的血管生成范例被认为是E2诱导的血管形成的原因。E2诱导模型中的新血管形成的研究将提供在生理相关背景下检查这些机制的机会，从而识别某些负责出生后新血管形成的基本机制。

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.