Platelets Are Novel Regulators of Neovascularization and Luteinization during Human Corpus Luteum Formation

Department of Gynecology and Obstetrics, Kyoto University, Kioto, Kyōto, Japan
Endocrinology (Impact Factor: 4.5). 08/2007; 148(7):3056-64. DOI: 10.1210/en.2006-1687
Source: PubMed


The human corpus luteum is a unique endocrine organ that is periodically constructed from the ovulated follicle. During human corpus luteum formation, which is well known as a pathophysiological model for tissue remodeling, the precise mechanisms by which centripetal vascular development is regulated remain unknown. Recently platelets were reported to contain chemoattractive substances with the potential to induce endothelial migration. In this study, we examined the involvement of platelets in the early tissue remodeling process of the human corpus luteum. An immunohistochemical study demonstrated that considerable amounts of red blood cells and CD41-positive platelets were localized at extravascular sites among luteinizing granulosa cells after ovulation. Platelet deposition gradually decreased and became limited near the central cavity toward which microvessels were extending. Platelets were hardly observed in the midluteal phase when the vascular network had already been established. These platelets expressed CD62P/P-selectin and were colocalized with extracellular matrix, suggesting that platelets had been activated by the extracellular matrix. Progesterone production by luteinizing granulosa cells that were isolated from patients undergoing in vitro fertilization therapy was significantly promoted by direct contact with platelets during 4-d culture. Platelet-derived soluble factors induced spreading in granulosa cell morphology. These factors also increased the migration of human umbilical vein endothelial cells, whereas luteinizing granulosa cells attenuated platelet-induced endothelial cell migration. These findings lead us to propose the novel concept that platelets are regulators of endothelial cell migration and granulosa cell luteinization in the remodeling process of the human corpus luteum.

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    • "Moreover, the blood clot formed during ovulation might stimulate cell migration. Indeed, platelets are a better stimulant for endothelial cells migration than granulosa cells themselves [19]. Examples of proangiogenic cytokines acting on this stage of the cycle include the cytokines fibroblast growth factor 2 (FGF2), VEGF, platelet-derived growth factor (PDGF) family, and angiopoietin (Ang). "
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    ABSTRACT: In adults, physiological angiogenesis is a rare event, with few exceptions as the vasculogenesis needed for tissue growth and function in female reproductive organs. Particularly in the corpus luteum (CL), regulation of angiogenic process seems to be tightly controlled by opposite actions resultant from the balance between pro- and antiangiogenic factors. It is the extremely rapid sequence of events that determines the dramatic changes on vascular and nonvascular structures, qualifying the CL as a great model for angiogenesis studies. Using the mare CL as a model, reports on locally produced cytokines, such as tumor necrosis factor α (TNF), interferon gamma (IFNG), or Fas ligand (FASL), pointed out their role on angiogenic activity modulation throughout the luteal phase. Thus, the main purpose of this review is to highlight the interaction between immune, endothelial, and luteal steroidogenic cells, regarding vascular dynamics/changes during establishment and regression of the equine CL.
    Mediators of Inflammation 06/2013; 2013:420186. DOI:10.1155/2013/420186 · 3.24 Impact Factor
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    • "Stimulation of granulosa cells by hCG as well as by IGFs and hypoxia induced up-regulation of VEGF (Hazzard et al., 1999; Tropea et al., 2006; Taylor et al., 2007) that is cardinal for generation of healthy ovulatory follicles and CL (Distler et al., 2003). In addition to VEGF, other factors such as angiopoietin (1 and 2; (Sugino et al., 2005), leukocytes (Polec et al., 2011) and platelets (Furukawa et al., 2007; Nurden, 2007) contribute to the remodeling of endothelial cells and luteinized granulosa cells in the process of CL formation. In the current study we found that PEDF regulation is hormonally affected inversely to VEGF, further implying a role for PEDF as a negative regulator of ovarian angiogenesis. "
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    ABSTRACT: Angiogenesis is critical for the development of ovarian follicles. Blood vessels are abrogated from the follicle until ovulation, when they invade it to support the developing corpus luteum. Granulosa cells are known to secrete anti-angiogenic factors that shield against premature vascularization; however, their molecular identity is yet to be defined. In this study we address the physiological role of pigment epithelium derived factor (PEDF), a well-known angiogenic inhibitor, in granulosa cells. We have shown that human and mouse primary granulosa cells express and secrete PEDF, and characterized its hormonal regulation. Stimulation of granulosa cells with increasing doses of estrogen caused a gradual decrease in PEDF secretion, while stimulation with progesterone caused an abrupt decrease in its secretion. Moreover, We have shown, by time- and dose-response experiments, that the secreted PEDF and vascular endothelial growth factor (VEGF) were inversely regulated by human chorionic gonadotropin (hCG); namely, PEDF level was nearly undetectable under high doses of hCG while VEGF level was significantly elevated. The anti-angiogenic nature of PEDF secreted from granulosa cells was examined by migration, proliferation and tube formation assays in cultures of human umbilical vein endothelial cells (HUVECs). Depleting PEDF from primary granulosa cells conditioned-media accelerated endothelial cells proliferation, migration and tube formation.Collectively, the dynamic expression of PEDF that inversely portrays VEGF expression may imply its putative role as a physiological negative regulator of follicular angiogenesis.
    Molecular Human Reproduction 10/2012; 19(2). DOI:10.1093/molehr/gas046 · 3.75 Impact Factor
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    • "Indeed, peripheral blood lymphocytes and macrophages indicated a luteotrophic effect as these cells stimulated P secretion upon co-culture with granulosa cells [42-44]. Meanwhile, Furukawa et al. revealed that platelets are novel regulators of neovascularization and luteinization during the early luteal phase in humans [45]. An increased number of platelets localized to extravascular sites among luteinizing granulosa cells after ovulation and gradually decreased toward the mid luteal phase [45], that are similar to the PMN profile observed in the present study. "
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    ABSTRACT: After ovulation in the cow, the corpus luteum (CL) rapidly develops within a few days with angiogenesis and progesterone production. CL formation resembles an inflammatory response due to the influx of immune cells. Neutrophils play a role in host defense and inflammation, and secrete chemoattractants to stimulate angiogenesis. We therefore hypothesized that neutrophils infiltrate in the developing CL from just after ovulation and may play a role in angiogenesis of the CL. Polymorphonuclear neutrophils (PMN) were detected in CL tissue by Pas-staining, and interleukin-8 (IL-8, a neutrophil-specific chemoattractant) was measured in supernatant of the CL tissue culture: considerable amounts of PMNs and the high level of IL-8 were observed during the early luteal phase (days 1-4 of the estrous cycle). PMNs and IL-8 were low levels in the mid and late luteal phases, but IL-8 was increased during luteal regression. The PMN migration in vitro was stimulated by the supernatant from the early CL but not from the mid CL, and this activity was inhibited by neutralizing with an anti-IL-8 antibody, indicating the major role of IL-8 in inducing active PMN migration in the early CL. Moreover, IL-8 stimulated proliferation of CL-derived endothelial cells (LECs), and both the supernatant of activated PMNs and IL-8 stimulated formation of capillary-like structures of LECs. PMNs migrate into the early CL partially due to its major chemoattractant IL-8 produced at high levels in the CL, and PMNs is a potential regulator of angiogenesis together with IL-8 in developing CL in the cow.
    Reproductive Biology and Endocrinology 06/2011; 9(1):79. DOI:10.1186/1477-7827-9-79 · 2.23 Impact Factor
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