The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [(35)S]methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.

No abstract

Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.

The recently introduced intrauterine growth curve, based on ultrasonically estimated foetal weights, was retrospectively applied to an inborn population of 883 infants born before 33 gestational weeks at the University Hospital of Lund, during 1985-94. The estimation of birthweight deviation resulted in 630 (71.3%) infants with a birthweight appropriate for gestational age (AGA), 244 (27.6%) infants with a birthweight small for gestational age (SGA) and 9 (1.1%) infants with a birthweight large for gestational age. Birthweight deviation was associated with an increased mortality [odds ratio (OR) adjusted for gestational age 1.29 per SD (12%) change in birthweight for gestational age, 95% CI: 1.10-1.50; p = 0.002]. At gestational age 25-28 weeks, SGA-infants had an increased incidence of respiratory distress syndrome (RDS) as compared to AGA-infants (OR adjusted for gestational age: 1.98, 95% CI: 1.12-3.52; p = 0.019). At gestational age 29-32 weeks, SGA-infants had a lower incidence of RDS as compared to AGA-infants (OR adjusted for gestational age: OR 0.52, 95% CI: 0.34-0.80; p = 0.003). After adjustment for confounding variables, infants born at gestational age 25-28 weeks from mothers with pre-eclampsia, appeared to be a high-risk group for RDS, whereas at the age of 29-32 gestational weeks, negative birthweight deviation had a protective effect against RDS. Antenatal corticosteroid administration appeared to have a less beneficial effect on mortality, RDS and cerebral haemorrhage in infants born SGA vs in those born AGA.

Objective To investigate the proportion of women with findings characteristic for pre‐eclampsia, as opposed to renal disease, in a controlled study of hypertensive pregnant women undergoing antepartum renal biopsy. Design An observational prospective controlled study. Setting University Hospital of Lund, Sweden. Sample Thirty‐six previously healthy women with hypertensive disease in pregnancy, consecutively admitted to the antenatal ward at onset of disease during a 20 month period and giving informed consent, as well as 12 voluntary healthy pregnant controls. Methods Renal biopsy samples were obtained from all participants and evaluated by light microscopy, electron microscopy and immunofluorescence techniques. Main outcome measures Presence and degree of glomerular endotheliosis. Results Glomerular endotheliosis was present in all women with pre‐eclampsia and gestational hypertension, and in 5 of the 12 controls, although significant differences in the degree of endotheliosis were found between the groups. Clinically undetected renal disease was not diagnosed in any of the women. Conclusion Glomerular endotheliosis was found in women with normal pregnancy as well as in both non‐proteinuric and proteinuric hypertension and is consequently not, as earlier believed, pathognomonic for pre‐eclampsia. The transition between normal term pregnancy, gestational hypertension and pre‐eclampsia appears to be a continuous process, perhaps of increasing adaptation to pregnancy. Pre‐eclampsia may be the extreme of the adaptational process, rather than a separate abnormal condition. Clinically undetected renal disease could be a rare cause of hypertension in pregnancy.