Christoph Keck

Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors

It was shown before that the soluble form of VEGFR-1 (sVEGFR-1) is present in serum of pregnant women. The aim of the present study was to investigate the presence of this endogenous vascular endothelial growth factor-A (VEGF-A) antagonist in human serum in more detail. sVEGFR-1 was detected in human serum and plasma from normal healthy male and female donors by ELISA. sVEGFR-1 levels ranged from non-detectable up to 440 pg/ml, with no significant difference between male and female donors. In addition, vein endothelial cells (ECs) from an intact vascular bed, the umbilical cord, were shown to secrete sVEGFR-1. Furthermore, human peripheral blood monocytes, a non-EC type expressing VEGFR-1, were shown to contribute to the sVEGFR-1 detectable in human serum and plasma for the first time. EC- and monocyte-derived sVEGFR-1 proved capable of inhibiting the VEGF-induced proliferation and migration of ECs in vitro. Finally, secretion of sVEGFR-1 was increased by the angiogenic factor basic fibroblast growth factor (bFGF) in human ECs and was also enhanced in lipopolysaccharide-activated human monocytes. In human umbilical vein endothelial cells, both the membrane-bound and the sVEGFR-1 seem to be equally regulated on the mRNA as well as the protein level. The presence of an sVEGFR-1 in human serum and plasma of normal male and female donors strongly suggests that it plays an important role as a naturally occurring VEGF antagonist in the regulation and availability of VEGF-mediated biological activities in vivo.

Body Mass Index but Not a Polymorphism of the Interleukin-1 Receptor Antagonist (IL-1 RA) Gene Is Associated with Age at Natural Menopause

Background: A genetic component of the onset of menopause has been described and several candidate genes have been identified. We hypothesized that carriage of a polymorphism of the interleukin-1 receptor antagonist gene (IL-1 RA) is associated with an early age at menopause. Methods: In a prospective cohort study, 90 consecutive postmenopausal Caucasian women were genotyped by PCR for the presence of an 86-base pair tandem repeat polymorphism in intron 2 of IL-1 RA. Results: We found that 36/90 (40%) women were homozygous for the wild-type allele 1 and 49/90 (54%) women were heterozygous for any of the variant alleles (1/2 [n = 44], 1/3 [n = 3], 2/3 [n = 2]). Two women (2%) were homozygous carriers of the variant allele 2. The wild-type allele 1 was identified on 119 of 180 chromosomes for an allele frequency of 0.66. The polymorphic alleles 2 and 3 were present on 56 and 5 chromosomes, respectively (allele frequencies 0.31 and 0.03, respectively). No correlation between the IL-1 RA genotype and the age at menarche and menopause, the length of the reproductive period, and the number of deliveries and miscarriages was ascertained. As to allele frequencies, homozygous and heterozygous carriers of the variant allele 2 had a median age at menopause of 50 (range 40–48) years, compared to 49.5 (range 39–56) years for women with no allele 2 (p value 0.41). Women with at least one allele 2 had a median age at menarche of 13 (range 10–16) years, compared to 13 (range 10–17) years for women with no allele 2 (p value 0.1). Decreasing body mass index, but not smoking, was correlated with an increasing age at natural menopause (r = –0.23, p = 0.04). Conclusions: Our preliminary data suggest that an 86-base pair tandem repeat polymorphism in intron 2 of IL-1 RA does not modulate the onset and cessation of menses in this cohort of Caucasian women.