Lymphocyte contributions to altered endometrial angiogenesis during early and midgestation fetal loss

Abstract

Peri-implantation and midgestational fetal losses reduce potential litter sizes up to 40% in commercial swine. Peri-implantation studies [gestation days (gd)15-23] of porcine RNA from laser capture microdissected uterine lymphocytes and biopsies of mesometrial endometrium and trophoblast previously linked gd21-23 fetal arrest with transcriptional deficits in vascular endothelial growth factor (VEGF) and its regulatory factor, hypoxia inducible factor (HIF)-1alpha, and with elevations in IFN-gamma and TNF-alpha and suggested endometrial lymphocytes played a pivotal, proangiogenic role in fetal survival. Here, we address more comprehensively porcine endometrial angiogenesis by comparing transcription between endometrial endothelium and lymphocytes during early (gd20) and midgestation (gd50) losses and by incorporation of histopathology and protein immunolocalization of VEGF, placenta growth factor (PlGF), VEGF receptor I (VEGFRI), and VEGFRII. In healthy sites, endometrial lymphocytes transcribed more VEGF at gd50 than gd20, and transcripts were more abundant in lymphocytes than in endothelium or trophoblast. Arterial endothelial cells showed the most abundant transcription of PlGF. With fetal arrest, maternal transcripts for VEGF but not PlGF dropped, and fetal transcripts remained relatively stable. Maternal and fetal HIF-1alpha transcription declined. Lymphocytes preferentially transcribed VEGFRI over VEGFRII, and endometrial arterial endothelium and trophoblast preferentially transcribed VEGFRII. IFN-gamma and TNF-alpha transcripts were present in gd20 and gd50 healthy- and arresting-implantation sites. gd20 arrest was associated with greater transcription of IFN-gamma than TNF-alpha in maternal and fetal tissues. At gd50, this was reversed. Endometrial, vascular pathology was evident only at gd50. These data suggest the critical importance for lymphocyte-driven endometrial angiogenesis, which extends to midgestation.

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

“…The hemodynamic and angiogenic influences lymphocytes and their products are emerging areas and further investigations are needed to understand how central their roles are for initiation and progression of preeclamptic pathology. 8,[34][35][36][37] Impaired SA remodeling is a key feature found amongst the "great obstetrical syndromes" . 38 In mice, we clearly show that, over the normal term of pregnancy, a maternal-fetal partnership exists that can resolve the hemodynamic changes imposed by this arterial pathology.…”

Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig

“…In addition, the conceptus contributes to synthesis of VEGFA since its expression increases gradually until day 16 of pregnancy (Kaczmarek et al 2009). Transcription profiles for endometrial lymphocytes indicate that lymphocytes contribute to and regulate angiogenesis through transcription of VEGFA, hypoxia inducible factor 1 a, and IFNG (Tayade et al 2007). During implantation period, number of uterine natural killer (NK) cells increases in the porcine endometrium.…”

“…Overactivation of inflammatory pathways leads to the onset of reproductive disorders or diseases (Jabbour et al 2009). For example, in pigs, highly localized and abundant expression of interferon g (IFNG), tumor necrosis factor a (TNF), and interleukin 1b (IL1B) in the endometrium is associated with arrested conceptus development between days 15 and 23 of pregnancy (Tayade et al 2007, Croy et al 2009). Cytokines are involved in the proliferation, differentiation, and cell survival that play a role in conceptus growth and implantation.…”

Natural killer cell-triggered vascular transformation: maternal care before birth?

“…27 The highest numbers of Pgf transcripts are found in immature uNK cells with few granules. 28 We hypothesized that the role of angiogenic uNK cells is to locate the site of blastocyst implantation and to move towards it, thereby creating a 'custom made' guidance system for maternal vascular growth into an implantation site. We examined decidual expression of epidermal growth factor-like domain 7 (EGFL7), a key molecule in endothelial progenitor cell guidance and movement during blood vessel formation.…”

“…This role of lymphocytes appears to be conserved across species that have forms of placentation other than the hemochorial placentae discussed in this review. 28 Understanding of the potential for immune cells to function in angiogenesis and in circulatory regulation and the mechanisms that physiologically link the immune and cardiovascular systems is an important new horizon in health research. …”