In vivo dynamic MRI measurement of the noradrenaline-induced reduction in placental blood flow in mice.

PURPOSE: We developed a new model for in vivo placental perfusion measurements based on dynamic MRI in mice. As noradrenaline has been implicated in the pathogenesis of preeclampsia, we examined whether it reduced placental perfusion in mice, and whether such a reduction could be detected with our MRI model. MATERIALS AND METHODS: Mice at 16 days of gestation were injected intramuscularly with saline or noradrenaline solution. A conventional gadolinium chelate was then injected IV, and a single-slice T1-weighed 2D Fast SPGR sequence was acquired for 200 s. Signal intensity was measured on all the images and converted into contrast agent tissue concentrations in the maternal left ventricle (input function) and placentas. A one-compartment model was developed using compartmental and numerical modeling software. Mean blood flow (F) was calculated from a transfer constant. RESULTS: Twenty-six mice were studied, yielding a total of 55 MRI measurements of placental perfusion (29 in the control group and 26 in the noradrenaline group). Mean placental blood flow (F) was significantly lower in the noradrenaline group (0.72+/-0.84 ml/min/g of placenta) than in the control group (1.26+/-0.54 ml/min/g of placenta). CONCLUSION: Noradrenaline reduces placental perfusion in mice. Our MRI dynamic model might be useful for detecting and investigating abnormal placental blood flow, thereby avoiding the need for invasive procedures and animal sacrifice.

[Placental functional assessment using MRI: mice today, humans tomorrow?]. / L'IRM fonctionnelle pour l'étude de la fonction placentaire: aujourd'hui chez la souris, demain chez l'homme?

Placental insufficiency, a process due to either poor placental perfusion or permeability, may lead to progressive deterioration in placental function and materno-fetal morbidity. Advances in MR contrast media pharmacokinetic studies of transit through tissues and dynamic MRI allow to characterize organs microcirculation in vivo. Placental function assessment might be achieved using analysis of dynamic contrast enhanced MRI of tracers. A murine model of placental assessment has been constructed. Herein, principles, results and limitations of such techniques are discussed as well as their potential interest and weaknesses in humans.

Developmentally regulated expression of the murine ortholog of the potassium channel KIR4.2 (KCNJ15).

The gene KIR4.2 (K(+) inwardly rectifying channel 4.2) has been recently identified in the Down syndrome Chromosome Region 1. We have cloned the mouse ortholog of KIR4.2 and characterized its expression pattern. In situ hybridization showed a restricted and developmentally regulated pattern of expression. The expression is starting at E12.5 and expands at E14.5 in different tissues and organs, which may be affected in Down syndrome: heart, thymus, thyroid gland, and perichondrium. At E17.5, additional epithelia (kidney, bladder, stomach, lung) expressed also strongly the gene.

Construction of a 2.5-Mb integrated physical and gene map of distal 21q22.3.

The gene-rich telomeric region of 21q harbors several loci relevant to human diseases including autoimmune polyglandular disease type I, nonsyndromic deafness, Knobloch syndrome, holoprosencephaly, and bipolar affective disorder. A contig of genomic clones in this region would facilitate the isolation of these genes. However, distal 21q22.3 has yet been poorly mapped, presumably due to the presence of sequences that are underrepresented in yeast artificial chromosome (YAC) libraries. We generated a framework of YACs and used these clones as starting points for the isolation of a combination of bacterial artificial chromosome clones, P1-derived artificial chromosome clones, and cosmid clones by chromosome walking procedures. These studies resulted in the construction of a high-resolution contig map spanning the 2.5-Mb region from PFKL to the telomere, approximately 2 Mb of which are covered by ready-to-sequence contigs. Within this map we determined the location and relative distance of 21 markers. These include 9 established genetic markers, the order of which is cen-PFKL-D21S154-D21S170-D21S171-D21S1903- D21S1897- D21S112-D21S1446-D21S1575-tel. Moreover, we established the precise map position of 13 genes and 4 ESTs including the recently isolated genes C21ORF2, SMT3H1, RNA editing deaminase 1 (ADARB1), folate transporter (SLC19A1), COL18A1, lanosterol synthase (LSS-PEN), pericentrin (PCNT), and arginine methyltransferase (HRMT1L1). This integrated map provides a useful resource for the mapping and isolation of disease genes and for the construction of a complete transcription map of distal 21q as well as for large-scale sequencing efforts.

Mapping the Down syndrome chromosome region. Establishment of a YAC contig spanning 1.2 megabases.

The triplication of a region of chromosome 21 around D21S55 in 21q22.2-22.3 has been involved in the main features of Down syndrome including mental retardation (Down syndrome chromosome region: DCR). To improve the physical map of this region, we screened yeast artificial chromosome (YAC) libraries with ETS2 and ERG sequences. Five selected clones were analyzed by AluPCR, pulsed-field gel electrophoresis, and in situ hybridization. A 1.2-Mg contig, encompassing the protooncogenes ETS2 and ERG, was identified, its restriction map established and compared to the genomic map. ERG is distal to D21S55 and proximal to ETS2. ERG and ETS2 genes are 400 kb apart and in opposite orientations. The contig contains the distal boundary and part of the DCR. Three putative HTF islands were identified.