Expression of VEGF and Its Receptors in the Bovine Endometrium Throughout the Estrous Cycle: Effects of VEGF on Prostaglandin Production in Endometrial Cells

Tasaki, Yukari; Nishimura, Ryo; Shibaya, Masami; Lee, Hwa Yong; Acosta, Tomás J.; Okuda, Kiyoshi

doi:10.1262/jrd.09-139s

Cited by 27 publications

(23 citation statements)

References 41 publications

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“…In the mare, VEGF, VEGFR1 and VEGFR2 together facilitate the development of maternal and fetal vascular networks for the interchange of gases, nutrients and waste products throughout gestation [24]. In the bovine endometrium, VEGF and its receptors were regulated throughout the estrous cycle [25]. A study in the rhesus monkey during early pregnancy also indicated that VEGF-VEGFR pairs were involved in the process of trophoblast invasion, maternal vascular transformation and fetoplacental vascular differentiation and development [26].…”

Section: Discussionmentioning

confidence: 99%

Seasonal Changes in Immunoreactivity of Vascular Endothelial Factor and its Receptors VEGFR1 and VEGFR2 in the Uterus of Wild Ground Squirrels (<i>Citellus dauricus</i> Brandt)

Weng

Sheng

et al. 2012

Journal of Reproduction and Development

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Abstract. In this study, we investigated the immunoreactivity of vascular endothelial growth factor (VEGF) and its receptors flt-1 (VEGFR1) and the kinase domain receptor (KDR/Flk-1, VEGFR2) in the uteri of the wild ground squirrels during the estrous period, early pregnancy and nonbreeding period. Cellular localizations of VEGF, VEGFR1 and VEGFR2 were detected by immunohistochemistry, and total proteins were extracted from uterine tissue in the estrous period, early pregnancy and nonbreeding period for Western blotting analysis. In addition, plasma estradiol-17β and progesterone concentrations were measured by radioimmunoassay. Stronger positive staining of VEGF was found in luminal epithelial cells and glandular cells, and its receptors (VEGFR1 and VEGFR2) were observed in stromal cells in the estrous period and early pregnancy compared with the nonbreeding period. The protein levels of VEGF, VEGFR1 and VEGFR2 were significantly higher in the estrous period and early pregnancy as compared with the nonbreeding period. Besides, plasma estradiol-17β and progesterone concentrations were higher in the estrous period and early pregnancy than in the nonbreeding period, suggesting that the immunoreactivities of VEGF, VEGFR1 and VEGFR2 were correlated with changes in plasma estradiol-17β and progesterone concentrations. These results suggested that VEGF and its receptors may be involved in the regulation of seasonal changes in the uterine functions of wild female ground squirrels. Key words: Uterus, VEGF, VEGFR1, VEGFR2, Wild ground squirrel (J. Reprod. Dev. 58: [537][538][539][540][541][542][543] 2012) D uring the reproductive cycle, the uterine endometrium undergoes a precisely timed complex sequence of physiological and morphological changes in preparation for implantation. These changes are controlled primarily by the ovarian steroid hormones 17β-estradiol (E 2 ) and progesterone [1]. During pregnancy, blood flow to the uterus is increased dramatically to meet the rising demands of the growing fetus. Endocrine control of this phenomenon is complex but includes in part the action of many growth factors [2,3]. Vascular endothelial growth factor (VEGF) is a protein with angiogenic activity and a potent stimulator of microvascular permeability [4,5]. It plays an important role in physiological and pathological neovascularization via its receptors Flt1/VEGFR1 and kinase insert domain containing region (KDR)/VEGFR2, both of which have tyrosine kinase activity [6]. In reproductive organs, VEGF is required for normal ovarian angiogenesis and endometrial growth throughout the ovulatory cycle in humans [7,8] and rodents [9,10]. The expression of VEGF and its receptors has been demonstrated in the endometrium in humans and in experimental and domestic animals throughout the menstrual cycle, with an upregulation in the late proliferative and luteal phases [11][12][13][14][15], periods that correspond to angiogenesis and an increase in vascular permeability [16]. However, the expression of VEGF and its receptors VEGFR1 and V...

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Section: Discussionmentioning

confidence: 99%

Seasonal Changes in Immunoreactivity of Vascular Endothelial Factor and its Receptors VEGFR1 and VEGFR2 in the Uterus of Wild Ground Squirrels (<i>Citellus dauricus</i> Brandt)

Weng

Sheng

et al. 2012

Journal of Reproduction and Development

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“…those that encoded for growth factors/ cytokines or those involved in the progression of the estrous cycle. The expression of insulin-like growth factor 2; IGFII, insulin-like growth factor binding protein 2, 36 kDa; IGFBP2 [48], prostaglandin E receptor 2 (subtype EP2), 53 kDa; PTGER2 [49], vascular endothelial growth factor receptor 2; VEGFR2 [50] in the endometrium, increases during the elongation stage of conceptus development while the expression of ESR1 [51], matrix metallopeptidase 2 (gelatinase A, 72 kDa type IV collagenase; MMP2 [52], and VEGF [50] declines. Treatment with exogenous progesterone increased the expression of uterine serpins [53] as well as PGR, ESR1 and retinol binding protein 4, plasma; RBP4 [54].…”

Section: Cycle Related Changesmentioning

confidence: 99%

Transcriptomic Analysis of the Bovine Endometrium: What is Required to Establish Uterine Receptivity to Implantation in Cattle ?

2012

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Abstract. In cattle, the majority of pregnancy loss can be attributed to early embryonic loss which occurs prior maternal recognition of pregnancy on Day 16 (Day 0 = ovulation). During this time, carefully orchestrated spatio-temporal alterations in the transcriptomic profile of the endometrium are required to drive conceptus elongation, via secretions from the endometrium (termed histotroph) and establish uterine receptivity to implantation. The two main modulators of these processed are progesterone (P4) and the pregnancy recognition signal interferon tau (IFNT). Altered concentrations of P4 in circulation mediate its effects via the endometrium and have been associated with different rates of conceptus elongation in cattle. Transcriptomic analysis of the endometrium has shown that modulation of circulating P4 alters endometrial expression of genes that can contribute to histotroph composition, which is beneficial (when P4 is supplemented) or detrimental (when P4 is reduced) to the developing conceptus. In addition, down-regulation of the progesterone receptor, required to establish uterine receptivity, is altered in the endometrium of heifers with altered P4 concentrations. IFNT, a type 1 interferon, also significantly impacts on the endometrial transcriptome. It induces the expression of a large number of classical interferon stimulated genes as early as Day 15 of pregnancy. In summary, the successful establishment of pregnancy in cattle requires a sequence of key events to ensure appropriate maternally derived secretions, establish uterine receptivity to implantation as well as an adequate endometrial response to IFNT production. Key words: Estrous cycle, Gene expression, Pregnancy, Progesterone (J. Reprod. Dev. 58: [189][190][191][192][193][194][195] 2012) I n cattle, as in other ungulate ruminants, the implantation process is characterized by a protracted period of elongation of the hatched blastocyst followed by apposition, attachment and adhesion of the trophectoderm to the uterine luminal epithelium (LE) [1,2]. Following successful fertilisation of an oocyte in the oviduct, the resulting embryo enters the uterus on approximately day 4 of pregnancy where it undergoes a number of cell divisions to form the morula which, after further differentiation, forms a blastocyst consisting of the inner cells mass (which will eventually give rise to the embryo/foetus) and an outer cell mass consisting of trophectoderm cells which ultimately give rise to the placenta. Up to the blastocyst stage of development, the embryo is relatively autonomous i.e. contact with the maternal uterine environment is not strictly required, as evidenced by the fact it is possible to culture embryos in vitro up to the blastocyst stage of development. However, once the embryo hatches from the zona pellucida (approximately day 9-10), significant morphological changes occur in the conceptus of domestic animals, including cattle, that differentiate the early pregnancy events from those of rodents, humans and non-human primates. The hatch...

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“…The expression of some cytokines, growth factors and their receptors by endometrial cells are regulated by ovarian steroidal hormones (Robertson, 2007, Guzeloglu-Kayisli et al, 2009. Within the targeted transcripts, an angiogenic cytokine such as VEGF is up-regulated during oestrus, enabling higher endometrial blood flow, angiogenesis and vascularization as required for endometrial growth during the proliferation and differentiation of epithelial and stromal cells (Tasaki et al, 2010). Likewise, a pro-inflammatory cytokine mediator PTGS2 is up-regulated during late luteal phase as a precursor for PGF2 synthesis from arachidonic acid (AA), playing a role in the initiation of luteolysis (Skarzynski et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The repair mechanism also includes a remodelling of the vasculature and restoration of oxygen to the hypoxic tissue. The phagocytosis of apoptotic neutrophils by macrophages stimulates the secretion of VEGF, which enhances tissue angiogenesis, revascularisation and wound repair (Tasaki et al, 2010).…”

Section: Effects Of Endometrial Sampling On Uterine Healthmentioning

confidence: 99%

“…Additional cytokines and growth factors released during the resolution phase include immunosuppressive and antiinflammatory interleukin-10 (IL10) that inhibits the production of pro-inflammatory cytokines (Schneider et al, 2004); factors that stimulates the phagocytic activity of neutrophils and enhance tissue resolution (granulocyte-macrophage colony stimulating factor, GM-CSF2 (Becher et al, 2016); key vasoactive enzyme molecules which mediate the synthesis of prostaglandins (prostaglandin-endoperoxide synthase 2, PTGS2) (Arosh et al, 2002).) and growth factors that enhances angiogenesis, revascularisation and wound repair (vascular endothelial growth factor, VEGF) (Tasaki et al, 2010) (Tizard, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Effect of endometrial biopsy on uterine health in tropically adapted beef cattle

Garzon¹,

Orlando²

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In cattle, early embryonic loss during the first two to three weeks after fertilisation is recognised as the major cause of reproductive failure, with consequent significant impacts on business performance of beef and dairy farms. Inadequate endometrial receptivity is considered an important cause of early embryonic mortality in cattle. A pilot experiment was conducted to compare the outcome of performing different endometrial sampling procedures in tropically adapted (Bos indicus x Bos taurus) heifers, and to select the most suitable method to collect samples for investigation of endometrial gene expression. Endometrial biopsy (EB) using a biopsy device with a diameter similar to an artificial insemination gun (10366L Karl Storz®, Germany) was found to be the most reliable method of collecting endometrial samples in these heifers, with the samples recovered yielding a mean concentration of RNA of 72.9 ±39.3 ng/µl and mean RNA integrity number (RIN) of 7.3 ±1.1.To assess the likely safety of conducting EB in cattle a systematic review of published information assessing the impact of EB on subsequent pregnancy rates was conducted. Using the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) protocol, online searches identified 1164 possible studies. After applying the exclusion criteria, six studies allowed the comparison of pregnancy rates between sampled (n= 1,208) and non-sampled cows (n=2,393). The results showed that EB can be performed before breeding without adversely affecting the likelihood of cows becoming pregnant.A major objective of the research was to determine whether EB and evaluation of endometrial gene expression could be used to identify tropically adapted embryo transfer (ET) recipients more likely to become pregnant. Three potential EB scenarios were investigated, 1) EB on Day 7 of the oestrous cycle prior to the cycle when ET would be performed, 2) EB on Day 4 of the oestrous cycle in which ET would be performed i.e. EB 3 days before ET, and 3) EB on the same day when ET would be performed.The first study assessed the morphological and inflammatory changes induced by endometrial biopsy. Pre-synchronised heifers underwent EB from the horn ipsilateral to the corpus luteum (CL) either at Day 7 of the previous cycle (Group 1 n=10) followed by administration of a luteolytic dose of prostaglandin F2α or at Day 4 (Group 2, n=7) of the present cycle. All heifers were slaughtered on Day 7 of the present cycle. The site of EB was visually evident in 40% (4/10) of Group 1 and 42% (3/7) of Group 2 heifers. Histological assessment revealed no evidence of changes indicative of endometritis in either the biopsied or non-biopsied horns in both groups. The histological iii changes observed included mild mononuclear infiltration of the epithelium and mild vascular changes associated with haemorrhage and congestion.Initial investigation of the endometrial expression of the pro-inflammatory cytokine IL1β and wound healing cytokine TGFβ genes found no significant difference betwe...

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Expression of VEGF and Its Receptors in the Bovine Endometrium Throughout the Estrous Cycle: Effects of VEGF on Prostaglandin Production in Endometrial Cells

Cited by 27 publications

References 41 publications

Seasonal Changes in Immunoreactivity of Vascular Endothelial Factor and its Receptors VEGFR1 and VEGFR2 in the Uterus of Wild Ground Squirrels (<i>Citellus dauricus</i> Brandt)

Seasonal Changes in Immunoreactivity of Vascular Endothelial Factor and its Receptors VEGFR1 and VEGFR2 in the Uterus of Wild Ground Squirrels (<i>Citellus dauricus</i> Brandt)

Transcriptomic Analysis of the Bovine Endometrium: What is Required to Establish Uterine Receptivity to Implantation in Cattle ?

Effect of endometrial biopsy on uterine health in tropically adapted beef cattle

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