Hypoxia inducible factor-1α (HIF-1α) stimulates expression of genes associated with angiogenesis and is associated with poor outcomes in ovarian and other cancers. In normoxia, HIF-1α is ubiquitinated and degraded through the E3 ubiquitin ligase, von Hippel-Lindau; however, little is known about the regulation of HIF-1α in hypoxic conditions. FBW7 is an E3 ubiquitin ligase that recognizes proteins phosphorylated by glycogen synthase kinase 3β (GSK3β) and targets them for destruction. This study used an ovarian cancer cell model to test the hypothesis that HIF-1α phosphorylation by GSK3β in hypoxia leads to interaction with FBW7 and ubiquitin-dependent degradation. Expression of constitutively active GSK3β reduced HIF-1α protein and transcriptional activity and increased ubiquitination of HIF-1α in hypoxia, whereas pharmacologic inhibition of GSK3 or expression of siGSK3β promoted HIF-1α stabilization and activity. A mechanism through FBW7 was supported by the observed decrease in HIF-1α stabilization when FBW7 was overexpressed and both the elevation of HIF-1α levels and decrease in ubiquitinated HIF-1α when FBW7 was suppressed. Furthermore, HIF-1α associated with FBW7γ by co-immunoprecipitation, and the interaction was weakened by inhibition of GSK3 or mutation of GSK3β phosphorylation sites. The relevance of this pathway to angiogenic signaling was supported by the finding that endothelial cell tube maturation was increased by conditioned media from hypoxic SK-OV-3 cell lines expressing suppressed GSK3β or FBW7. These data introduce a new mechanism for regulation of HIF-1α during hypoxia that utilizes phosphorylation to target HIF-1α for ubiquitin-dependent degradation through FBW7 and may identify new targets in the regulation of angiogenesis.
Objective Pregnancy induces rapid, progressive and substantial changes to the cardiovascular system. The low recurrence risk of preeclampsia, despite familial predisposition, suggests an adaptation associated with pregnancy that attenuates risk for subsequent preeclampsia. We aimed to evaluate the persistent effect of pregnancy on maternal cardiovascular physiology. Study Design Forty-five healthy nulliparous women underwent baseline cardiovascular assessment preconception and repeated an average of 30 months later. After baseline evaluation, 17 women (Preg) conceived singleton pregnancies and all delivered at term. The remaining 28 women comprised the non-pregnant control group (NP). We measured mean arterial blood pressure (MAP), cardiac output (CO), plasma volume (PV), pulse wave velocity (PWV), uterine blood flow (UBF), and flow-mediated vasodilation (FMD) at each visit. Results There was a significant decrease in mean arterial pressure from the prepregnancy visit to postpartum in women with an interval pregnancy (prepregnancy: 85.3±1.8, postpartum: 80.5±1.8 mm Hg), with no change in NP subjects (visit 1: 80.3±1.4, visit 2: 82.8±1.4 mm Hg), (p = .002). Pulse wave velocity was significantly decreased in women with an interval pregnancy (prepregnancy: 2.73±0.05, postpartum: 2.49±0.05 m/s), as compared to those without an interval pregnancy (visit 1: 2.56±0.04, visit 2: 2.50±0.04 m/s), (p = .005). We did not observe a residual effect of pregnancy on cardiac output, plasma volume, uterine blood flow or flow-mediated vasodilation. Conclusion Our observations of decreased mean arterial pressure and reduced arterial stiffness following pregnancy suggest a significant favorable effect of pregnancy on maternal cardiovascular remodeling. These findings may represent a mechanism by which preeclampsia risk is reduced in subsequent pregnancies.
Objective To evaluate vascular dysfunction using both physiologic measures and biochemical markers, longitudinally, prior to and during pregnancy, in nulliparous women who had uncomplicated pregnancies compared to those who developed complicated hypertension during pregnancy. Methods Twenty healthy nulliparous women were studied during the follicular phase and in early (EP) and late (LP) pregnancy. All had singleton conceptions and delivered at term, seventeen with uncomplicated pregnancies (NP) and three who developed complicated hypertension (HP) after the LP evaluation. We compared prepregnancy, EP and LP pulse wave velocity (PWV) and soluble vascular cell adhesion molecule (sVCAM-1) between the NP and HP groups. PWV was measured using ultrasound and simultaneous echocardiogram tracing then calculated as the estimated distance divided by interval between EKG r-wave peak and peak brachial artery flow. SVCAM-1 was measured using a commercially available kit. Data are means ± SE, significance accepted as p < 0.05. Results The NP group had significantly lower prepregnant PWV (NP: 2.66 ± 0.06 m/s, HP: 3.00 ± 0.04, p=.02), but PWV was not different at the EP or LP time points. SVCAM-1 was significantly lower prior to pregnancy and during EP and LP in the NP group (Prepregnancy: NP: 712 ± 32 ng/mL, HP: 1058 ± 107, p < .001; EP: NP: 695 ± 31 ng/mL, HP: 924 ± 52, p = .004; LP: NP: 663 ± 25 ng/mL, HP: 946 ± 36, p < .001). Conclusions PWV and sVCAM-1 may be important prepregnancy discriminators useful in assessing risk for preeclampsia prior to pregnancy.
We examined the relationship between prepregnant pulse pressure (PP), mean arterial pressure (MAP), cardiac output (CO)/PP, a measure of arterial compliance, and development of complicated hypertension during pregnancy (CH) with the goal of identifying a potential predictor of CH. Twenty nulliparous subjects were studied before pregnancy; seventeen had normal pregnancies (CTL) and three CH. Blood pressure monitoring was performed using tonometry. CO was determined by Doppler echocardiograph. Data are expressed as mean±SD. Prepregnant PP was significantly higher in CH subjects (CH: 58.3±6.3, CTL: 46.2±1.7 mmHg; p = 0.02). CO/PP was significantly lower in CH subjects (CH: 6.9 ± 1.8, CTL: 10.6 ± 2.8; p = 0.04). MAP was not significantly different. Increased PP before pregnancy may suggest increased risk for CH. With accurate prediction of CH before pregnancy initiation of preventative measures could begin earlier, either prior to, or in early pregnancy, potentially increasing preventative efficacy and decreasing CH.
Stillbirth remains a global health challenge which is greatly affected by social and economic inequality, particularly the availability and quality of maternity care. The International Stillbirth Alliance (ISA) exists to raise awareness of stillbirth and to promote global collaboration in the prevention of stillbirth and provision of appropriate care for parents whose baby is stillborn. The focus of this ISA conference was to share experiences to improve bereavement support and clinical care. These issues, relevant throughout the globe, are not discrete but closely interrelated, with both similarities and differences depending on the specific country and cultural context. Counting stillbirths and understanding the causes of stillbirth are essential not only for providing optimal care and support to parents whose babies die, but also for reducing the future burden of stillbirth. This summary highlights novel work from obstetricians, midwives, psychologists, parents and peer support organizations that was presented at the ISA meeting. It covers topics including the bereavement process, peer support for parents, support and training for staff, evidence for clinical care, and the need for accurate data on stillbirths and perinatal audits. Representatives from the maternity services of the region presented their outcome data and shared their experiences of clinical and bereavement care. Data and developments in practice within stillbirth and bereavement care must be widely disseminated and acted upon by those responsible for maternity care provision, both to prevent stillbirths and to provide high-quality care when they do occur.
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