Amy O. Robb

Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell‐to‐cell contact

The cytokine microenvironment is thought to play an important role in the generation of immunoregulatory cells. Nematode infections are commonly associated with Th2 cytokines and hyporesponsive T cells. Here we show that IL‐4‐dependent macrophages recruited in vivo by the nematode parasite Brugia malayi actively suppress the proliferation of lymphocytes on co‐culture in vitro. These alternatively activated macrophages block proliferation by cell‐to‐cell contact, implicating a receptor‐mediated mechanism. Further, the proliferative block is reversible and is not a result of apoptosis. Suppressed cells accumulate in the G1 and G2 / M phase of the cell cycle. Interestingly, the G1 and G2 / M block correlates with increased levels of Ki‐67 protein, suggesting a mechanism that affects degradation of cell cycle proteins. We also show that, in addition to lymphocyte cell lines of murine origin, these suppressive cells can inhibit proliferation of a wide range of transformed human carcinoma lines. Our data reveal a novel mechanism of proliferative suppression induced by a parasitic nematode that acts via IL‐4‐dependent macrophages. These macrophages may function as important immune regulatory cells in both infectious and noninfectious disease contexts.

Influence of the Menstrual Cycle, Pregnancy, and Preeclampsia on Arterial Stiffness

Arterial stiffness and compliance are major predictors of adverse cardiovascular events and are influenced by female sex hormones, including estrogen and progesterone. The aim of this longitudinal study was to evaluate the effect of the menstrual cycle, normal pregnancy, and preeclampsia on central and systemic arterial stiffness. Ten healthy nulliparous women with regular menses were studied in the early and midfollicular, periovulatory, and luteal phases of a single menstrual cycle. Twenty-two primigravida pregnant women were studied throughout pregnancy at 16, 24, 32, and 37 weeks gestation and at 7 weeks postpartum. Fifteen primigravida women with preeclampsia were studied at diagnosis and 7 weeks postpartum. Augmentation index and carotid-radial and carotid-femoral pulse wave velocities were measured using applanation tonometry. Augmentation index fell during the luteal phase of the menstrual cycle (luteal phase versus periovulatory phase; P<0.05). In normal pregnancy, pulse wave velocity and augmentation index increased from 24 weeks over the third trimester (P≤0.01 for both). All of the measures were increased in women with preeclampsia (P≤0.01), with augmentation index and carotid-femoral pulse wave velocity remaining elevated 7 weeks postpartum (P≤0.02). We conclude that systemic arterial stiffness undergoes major changes during the menstrual cycle and pregnancy and that preeclampsia is associated with greater and more prolonged increases in arterial stiffness. These effects may contribute to adverse cardiovascular outcomes of pregnancy and preeclampsia.

Influence of menstrual cycle on circulating endothelial progenitor cells

BACKGROUND Endothelial progenitor cells (EPCs) are circulating mononuclear cells that participate in angiogenesis. The aim of this study was to determine the influence of the menstrual cycle on the number and function of EPCs, and to investigate their relationship with circulating concentrations of sex steroids and inflammatory mediators. METHODS Ten healthy nulliparous, premenopausal, non-smoking women with regular menses were studied over a single menstrual cycle. Venepuncture was performed in the menstrual, follicular, peri-ovulatory and luteal phases. EPCs were quantified by flow cytometry (CD133(+)CD34(+)KDR(+) phenotype) and the colony-forming unit (CFU-EPC) functional assay. Circulating concentrations of estradiol, progesterone and inflammatory mediators (TNF-alpha, IL-6, sICAM-1 and VEGF) were measured by immunoassays. RESULTS The numbers of CD133(+)CD34(+)KDR(+) cells were higher in the follicular phase (0.99 +/- 0.3 x 10(6) cells/l) compared with the peri-ovulatory phase (0.29 +/- 0.1 x 10(6) cells/l; P < 0.05). In contrast, the numbers of CFU-EPCs did not vary over the menstrual cycle. There were no correlations between EPCs and concentrations of either circulating sex steroids or inflammatory mediators. CONCLUSIONS CD133(+)CD34(+)KDR(+) cells but not CFU-EPCs vary during the menstrual cycle. Our findings suggest a potential role for circulating EPCs in the normal cycle of physiological angiogenesis and repair of the uterine endometrium that is independent of circulating sex steroids or inflammatory mediators.

Endothelial progenitor cells in pregnancy

The discovery of endothelial progenitor cells has generated considerable interest in the field of vascular biology. These cells arise from a population of circulating mononuclear cells and have the capacity to form new blood vessels and contribute to vascular repair. Circulating endothelial progenitor cell numbers are reduced in patients with cardiovascular risk factors and in the presence of endothelial dysfunction, but are increased in response to ischaemia, oestrogens and drug therapy. They have been studied in pathologies from cardiovascular and renal disease to rheumatoid arthritis and pre-eclampsia. Pregnancy is a challenge to the maternal vascular system, requiring systemic adaptation and pronounced local changes in the uterus. Diseases of pregnancy such as pre-eclampsia and gestational diabetes increase the risk of pregnancy complications and are associated with endothelial dysfunction. We propose that endothelial progenitor cells have an important role in the regulation and maintenance of the vasculature during pregnancy. This review summarises our current understanding of endothelial progenitor cells, with specific reference to their role in angiogenesis and human pregnancy.

Acute endothelial tissue plasminogen activator release in pregnancy

Summary.  Objective: Pregnancy is associated with marked changes in vascular physiology and an increased risk of thrombosis. The aim of the study was to assess the effect of pregnancy on the acute release of tissue plasminogen activator (t‐PA) from the endothelium. Methods and results: Ten primigravida pregnant women were recruited in the third trimester of pregnancy (week 36 ± 1) and compared with 20 age‐matched non‐pregnant women (day 9.8 ± 0.3 of menstrual cycle). Blood flow and plasma fibrinolytic factors were measured in both forearms by venous occlusion plethysmography and blood sampling, respectively, during unilateral brachial artery infusions of bradykinin (100–1000 pmol min−1). Pregnant women had higher plasma plasminogen activator inhibitor type 1 (PAI‐1) antigen concentrations (77.1 ± 12.4 vs. 21.5 ± 9.8 ng mL−1; P = 0.004) that resulted in lower basal t‐PA/PAI‐1 ratios (0.2 ± 0.1 vs. 0.6 ± 0.1; P = 0.02) and plasma t‐PA activity concentrations (0.17 ± 0.02 vs. 0.58 ± 0.06 IU mL−1; P < 0.0004). In both groups, bradykinin caused dose‐dependent increases in blood flow and local release of plasma t‐PA antigen and activity (P < 0.005 for all). Both the plasma t‐PA/PAI‐1 ratios and the net release of active t‐PA were markedly reduced in pregnant women (P < 0.05 for both). Area under the curve for net active t‐PA release was reduced by 36%. Conclusions: Pregnancy is associated with major perturbations of endogenous fibrinolytic capacity with an overwhelming increase in plasma PAI‐1 concentrations and an inadequate release of active t‐PA. These prothrombotic effects may, in part, explain the increased risk of arterial and venous thrombosis in pregnant women.

The influence of the menstrual cycle, normal pregnancy and pre-eclampsia on platelet activation

Platelet activation has a key role in mediating thrombotic and inflammatory events. This study aimed to determine the influence of the menstrual cycle, pregnancy and pre-eclampsia on in vivo platelet activation. Twelve healthy nulliparous, non-smoking women with regular menses were studied over a single menstrual cycle. Twenty-one healthy primigravida pregnant women were studied longitudinally at 16, 24, 32 and 37 weeks gestation and seven weeks post-partum. Sixteen primigravida women with pre-eclampsia were studied at time of diagnosis and at seven weeks post-partum. Platelet-monocyte aggregates and platelet-surface P-selectin expression were assessed by flow-cytometry. Soluble P-selectin and CD40 ligand (CD40L) were measured by ELISA. Markers of platelet activation did not vary over the menstrual cycle. Platelet-monocyte aggregates were greater in the third trimester of pregnancy compared to non-pregnant women (p=0.003). Platelet surface and plasma soluble P-selectin concentrations increased with gestation (p<0.0001) and were raised by 24 weeks of pregnancy compared to non-pregnant women (p< or =0.02 for both) and together with platelet monocyte aggregates, decreased post-partum (p< or =0.02). Soluble CD40L concentrations fell in pregnancy, reaching a nadir at mid-gestation (p=0.002). There were no differences in markers of platelet activation between normal and pre-eclamptic pregnancies. In conclusion, platelet activation is increased in pregnancy and increases with gestation but is unaffected by pre-eclampsia. This suggests that systemic platelet activation is a feature of pregnancy but this is not affected by established pre-eclampsia.

Is the first urinary albumin/creatinine ratio (ACR) in women with suspected preeclampsia a prognostic factor for maternal and neonatal adverse outcome? A retrospective cohort study

The aim of this study was to determine the prognostic value of the first urinary albumin/creatinine ratio (ACR) for adverse maternal and neonatal outcomes and how it relates to other prognostic factors.