HT/PET-MPs (Gestational Hypertension and Preeclampsia/Toxemia-Microparticles) Affect Trophoblast and Endothelial Function (page 893)
Hypertensive disorders of pregnancy are common vascular pathologies having severe implications for maternal and fetal health. Unraveling the complex pathogenesis of gestational vascular complications is crucial for their prevention and improved management.
Previously, microvesicles (MVs) were shown to affect coagulation and inflammation in pregnancy. Our study demonstrates that MVs obtained from women with gestational hypertension and preeclampsia present higher levels of antiangiogenic proteins and proinflammatory cytokines. The present study shows that in contrast to MVs of healthy pregnant women, gestational vascular complication MVs do not induce early stage trophoblast migration (Figure S5), inhibit endothelial tube formation, and cause massive apoptosis in term trophoblasts. This indicates the involvement of MVs in placental development at early gestational ages and in placental health at late stages of pregnancy.
Recent studies suggested that LMWH (low molecular weight heparin) could improve the outcome of women with gestational vascular complications. The mechanisms through which LMWH exert its effect are multifaceted, involving maternal and placental anticoagulation, as well as anti-inflammatory and complement pathway activity. The findings of the current study highlight that MVs are a new critical player participating in physiological mechanisms of placental development and in the pathology of hypertensive disease in pregnancy. Furthermore, these data could foster our understanding of LMWH effects in this challenging clinical setting.
Amyloid-β Peptides (page 966)
Alzheimer disease (AD) is the most common form of dementia with 27 million known cases worldwide. Its incidence is rapidly increasing, and there are no effective treatments. The cause is essentially unknown. Initially, defective cholinergic signaling was implicated. Subsequently, the role of amyloid deposits and the amyloid precursor protein was added to the picture. Amyloid-β (Aβ) is a peptide of 36 to 43 amino acids that is processed from amyloid precursor protein. A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Apolipoproteins enhance the breakdown of Aβ, but APOE4 is not very effective, leading to an excess amyloid buildup in the brain. Tau proteins stabilize microtubules. They are abundant in neurons of the central nervous system. Hyperphosphorylated tau pairs with other threads of tau eventually forming neurofibrillary tangles inside nerve cell bodies. Viruses, prions, oxidative stress, biometal biology, and numerous other factors are also implicated in AD including small-vessel vascular disease. Could AD be in part a vascular disorder? Indeed, amyloid can cause abnormal vascular reactivity. We found that Aβ induced vasoconstriction of coronary arteries in Langendorff-perfused rat hearts. Aβ bound to the α1 adrenoreceptor, thereby inducing a signal-transduction cascade with cytosolic calcium and extracellular-related kinase phosphorylation in vascular smooth muscle cells. Thus, Aβ itself could be a vascular signaling molecule. Aβ induced vasoconstriction, decreased coronary blood flow, and exhibited α1 adrenoreceptor–mediated signaling. Nonetheless, an in vivo model is necessary to pursue translation of our findings. The implications from our work are that successful therapies directed at AD will probably contain a component addressing the participation of blood vessels. The α1 adrenoreceptor has appeal as a target because the compounds are clinically in use. Furthermore, our notion could be investigated epidemiologically.
Hypoxia and Development of Nephropathy (page 914)
It is well established that kidney hypoxia is present in diseases closely associated with development of nephropathy, such as diabetes mellitus and hypertension. The hypothesis that chronic kidney hypoxia results in the development of nephropathy was originally proposed in 1998 and has since gained increasing support. However, the specific contribution of kidney hypoxia for the development of nephropathy is difficult to determine because of the presence of confounding factors, such as hyperglycemia, hypertension, and oxidative stress. To identify the specific role of kidney hypoxia, Friederich-Persson et al treated normoglycemic control rats with dinitrophenol, a mitochondrial uncoupler, which increases the mitochondrial oxygen consumption. Consequently, treatment with dinitrophenol increased total kidney oxygen consumption and resulted in kidney hypoxia. Interestingly, this resulted in nephropathy evidenced as increased protein excretion and tubulointerstitial damage. Importantly, there was no hyperglycemia, hypertension, or increased oxidative stress levels after dinitrophenol treatment. Thus, the main conclusion was that kidney tissue hypoxia is an independent pathway for the development of nephropathy. Being able to detect and target early alterations in intrarenal oxygen metabolism may be important for patients at risk of developing nephropathy. As such, interventions to prevent excessive kidney oxygen consumption or to restore kidney tissue oxygen availability may prove beneficial in preventing nephropathy in patients.
- © 2013 American Heart Association, Inc.