VEGF-binding peptide ligands are incorporated into hydrogel microspheres and reduce the amount of growth factor in solution. VEGF binding affinity is enhanced by creating ligands with a dimer structure. The spheres are able to knock down VEGF-mediated HUVEC growth and reduce calcium signaling. The binding interaction is reversible, allowing the spheres to be used as a VEGF delivery vehicle. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Marmosets express a fetal zone during adrenal development but fail to produce significant amounts of C19 steroids in adulthood. It is not clear however if P450c17 regulation is different from that in humans/rhesus or the primary sequence is altered. To this end we isolated marmoset and rhesus adrenocortical cells, and treated the cells with known regulators of P450c17 expression for 48 h. P450c17 protein increased with Forskolin (F) treatment, but was marginally inhibited by AII (A) and TPA (T) alone. Combined A + F and T + F dramatically ablated the F response. Cortisol levels (EIA) increased upon F treatment and were inhibited by A and T. Combination of treatments partially inhibited the F‐induced response. The protein‐coding region of marmoset and rhesus P450c17 cDNAs were then isolated from adrenals using RT‐PCR/TA cloning. Marmoset P450c17 shows one amino acid deletion but otherwise shares 90.6% and 91.4% homologies with the human and rhesus cDNA sequences, and 82.4% and 85% homologies with the human and rhesus predicted AA sequences, respectively. Since marmoset adrenocortical cells exhibit similar endocrine function to rhesus, impaired 17,20‐lyase activity in the adult marmoset adrenal may in part be due to differences in the primary sequence.
Fetal growth restriction (FGR) has been associated with insufficient development of utero-placental vasculature, which could be identified using maternal placental blood volume measurements. This preliminary study uses ferumoxytol-enhanced MRI to measure placental blood volume of three FGR subjects using variable flip angle T1-mapping. Mean values of maternal fractional, placental, and total blood volumes are reported, as well as changes in placental R1 values between two time points after contrast injection. We observe local placental heterogeneities, including regions with low factional blood volume in the subjects.
The role increased vascular endothelial growth factor (VEGF) plays in vascular function during normal vs. preeclamptic pregnancy has been a source of some controversy of late. In this study, we seek to understand how VEGF 165 influences vasodilator production via Ca 2+ signaling mechanisms in human endothelial cells. We utilize human umbilical vein endothelial cells (HUVEC) as well as intact ex vivo human umbilical vein (HUV Endo) to address direct stimulation of Ca 2+ and NO by VEGF 165 alone, as well as the effect of VEGF 165 on subsequent ATP-stimulated Ca 2+ signaling and NO production. We show that VEGF 165 stimulates Ca 2+ responses in both HUVEC and HUV Endo, which results in a corresponding increase in NO production in HUV Endo. Longer-term VEGF 165 pretreatment then inhibits sustained Ca 2+ burst responses to ATP in HUVEC and HUV Endo. This is paralleled by a corresponding drop in ATP-stimulated NO production in HUV Endo, likely through inhibition of Cx43 gap-junction function. Thus, although VEGF 165 makes a small initial positive impact on vasodilator production via direct stimulation of Ca 2+ responses, this is outweighed by the greater subsequent negative impact on Ca 2+ bursts and vasodilator production promoted by more potent agonists such as ATP. Overall, elevated levels of VEGF 165 associated with preeclampsia could contribute to the endothelial dysfunction by preventing Ca 2+ bursts to other agonists including but not limited to ATP. NEW & NOTEWORTHY In this manuscript, we show that VEGF levels associated with preeclampsia are a net negative contributor to potential vasodilator production in both a human ex vivo and in vitro endothelial cell model. Therefore, pharmacological targeting of VEGF-stimulated signaling pathways could be a novel treatment modality for preeclampsia-related hypertension.
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