Rational Women with preeclampsia (PE) have compromised endothelial function (assessed by brachial artery flow‐mediated dilation) compared to normal women. Placental and uterine spiral artery endothelial dysfunction is seen in PE pregnancies. Human studies remain incomplete, as most approaches have been unable to eliminate neural, humoral, paracrine influences on vessel response. Direct evaluation of the placental arterioles will allow a more direct analysis of vasodilatory responses as related to the endothelial dysfunction in PE. Objective To study placental endothelial function in preeclamptic (PE) and normal placental vessels. Methods To examine the impact of PE on the microvascular function, isolated vessels from placentas of healthy and PE pregnancies were used for videomicroscopy. Endothelial‐dependent dilation to flow (FMD), acetylcholine (ACh) and smooth muscle‐dependent dilation to papaverine were evaluated. Data are presented as a percentage of maximum diameter and were analyzed with 2‐way ANOVA RM with statistical significance set at *p<0.05; data are expressed as mean ± SE. Results Vessels from PE patients resulted in impairment of FMD (control 71.% ±6.6%, PE 31.6%±10.7%*) and dilation to Ach (control 63.6%±9.4, PE 32.7±8.83%*). Smooth muscle‐dependent dilation to papaverine was unchanged between the two groups (Figure ). Conclusion Preliminary studies show impaired endothelial function in placental vessels of subjects with PE, compared to healthy controls, while smooth muscle function was not affected. Understanding the underlying mechanism(s) of vasodilation in placental vasculature will further the understanding the pathophysiology of PE. Support or Funding Information The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, Award NumberUL1TR001436. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the NIH. This project is funded by the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. Vessels from PE patients resulted in impairment of FMD and dilation to ACh. Smooth muscle‐dependent dilation to papaverine was unchanged between the two groups. Statistical significance denoted with *
Objective Treatment with BCR‐ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side‐effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR‐ABL TKIs imatinib and nilotinib causes endothelial dysfunction. Methods Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 µmol/L) or nilotinib (100 µmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re‐assessed in the presence of either the nitric oxide synthase inhibitor L‐NAME (100 µmol/L) or the H2O2 scavenger PEG‐Catalase (500 U/mL). Results Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L‐NAME in vehicle‐treated arterioles (max dilation = 47±29%). Conversely, L‐NAME had no effect on FMD in imatinib‐ or nilotinib‐treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG‐Catalase (max dilation = 29±11% and 29 ± 14%, respectively). Conclusion Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro‐inflammatory H2O2.
Background: Preeclampsia (PreE) is a significant global health burden which impacts 10 million pregnancies annually resulting in over a half million lost lives. Mitochondrial damage has previously been demonstrated to be present in PreE. A novel relationship may exist between preeclampsia and mitochondrial damage via the release of cell-free mitochondrial DNA (cf-mtDNA). Previous work in models of systemic hypertension shows cf-mtDNA mediated activation of TLR9 to be a key part of disease development. We aim to evaluate the level of TLR9 activation and ROS production in patients with and without PreE. Methods: To investigate whether PreE plasma contains increased levels of cell free DNA that can activate TLR9, HEK-Blue TM -hTLR9 reporter cell line (Invivogen) was treated with 3% plasma from either control or PreE patients. The TLR9 activator ODN2006 served as positive control (Fig.1, A&B). To investigate whether PreE plasma can stimulate production of ROS, HUVECs were treated in similar fashion and ROS was evaluated using Mitosox TM (Fig. 1, C&D). Results: Cells treated with PreE plasma demonstrated a 1.7-fold increase in TLR9 activation vs control (p=0.005, Fig. 1A&B). In addition, Mitosox TM signal indicated a 1.8-fold increase in ROS in PreE vs. control (p=0.066, Fig. 1C&D). Conclusion: We conclude that plasma from PreE patients contains higher levels of cf-mtDNA that stimulates inflammation response via TLR9 that promotes mitochondrial ROS production. This mechanism may present a novel target for treatment of Pre-E.
Preeclampsia (PreE) is complication of pregnancy, affecting 5% of pregnancies in the United States, and presenting a significant burden to our healthcare systems. Oxidative damage and dysfunction of the placental microcirculation has been implicated. Clinical trials of antioxidant therapies to treat PreE have failed. However, none of these studies have used targeted antioxidants. Given that vascular compromise in preeclampsia may be caused by mitochondrial dysfunction, we propose that MitoTEMPOL (MT), a mitochondrial-targeted superoxide dismutase mimetic, will restore endothelium-dependent vasodilation in human placental arterioles. Arterioles from the maternal portion of the placenta of average diameter 161.1 ± 11.1 μm were cannulated on glass micropipettes and constricted with 0.1-1.5 nM endothelin-1 and flow was generated with a pressure gradient across vessel reservoirs. Flow-mediated dilation (FMD) was measured by video-microscopy presented as % maximal diameter from baseline. Smooth muscle function was evaluated by exposure to 100 μM papaverine. Vessels from normal placentas dilated to flow by 70.2% ± 3.8% (n=11), whereas vessels from PreE placentas dilated to only 47.9% ± 5.6% (n=8, p=0.005). Exposure to 10 μM of MT for 30 minutes in the organ bath restored Pre-E vessel dilation to 80.0% ± 3.9% (n=6, p=0.0003 vs PreE). FMD in normal vessels was not affected by exposure to MT (75.9% ± 7.2%, n=4, p=0.84). Significance was evaluated by 2-way ANOVA, α = 0.05. MT restores endothelium-dependent vasodilation in PreE vessels. Further evaluation of other mitochondrial-targeted antioxidants could lead to novel therapeutic options to improve vascular function in PreE.
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