Treating Hypertension in Pregnancy.

Hypertension is present in about 10 % of all pregnancies. The frequency of chronic hypertension and that of gestational hypertension is increasing. The management of pregnant women with hypertension remains a significant, but controversial, public health problem. Although treatment of hypertension in pregnancy has shown to reduce maternal target organ damage, considerable debate remains concerning treatment. We review current evidence regarding treatment goals, the ideal treatment starting time, and which drugs are available for the treatment of hypertension in pregnancy.

AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase.

BACKGROUND: We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT1-AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT1-AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-kappaB (NF-kappaB) activation. METHODS AND RESULTS: We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT1-AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT1-AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT1-AA lead to NF-kappaB activation in VSMC and trophoblasts. AT1-AA activated NF-kappaB. Inhibitor-kappaBalpha (I-kappaBalpha) expression was reduced in response to AT1-AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-kappaB activation. VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-kappaB activation in response to Ang II and AT1-AA. The p22, p47, and p67 phox expression in placentas from preeclamptic patients was increased, compared with normal placentas. Furthermore, NF-kappaB was activated and I-kappaBalpha reduced in placentas from preeclamptic women. CONCLUSIONS: NADPH oxidase is potentially an important source of ROS that may upregulate NF-kappaB in preeclampsia. We suggest that AT1-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.

Activating auto-antibodies against the AT1 receptor in preeclampsia.

Immune mechanisms have been shown to be important in the pathogenesis of preeclampsia. Here, we review our studies of agonistic antibodies against the AT1 receptor in the pathogenesis as well as a pathologic phenotype of this disorder, focusing on observations in our laboratory. We have demonstrated their specificity of the binding by Western blotting, co-localization, and co-immunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including AP-1 and nuclear factor-kappaB (NF-kappaB) activation. The signaling results in tissue factor production and reactive oxygen species (ROS) generation, both of which have been implicated in preeclampsia. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proven with certainty. However, we believe the findings are compelling and warrant further study.

AT1 receptor agonistic antibodies, hypertension, and preeclampsia.

Immunologic mechanisms and putatively circulating mediators of preeclampsia are not a new idea, but are nevertheless compelling. Here we review studies relating to the role of agonistic antibodies that bind the second extracellular loop of the angiotensin II (AII) AT1 receptor in the pathogenesis as well as a pathologic phenotype of this disorder, focusing on observations in our laboratory. These agonistic autoantibodies (AT1-AA) appear with the development of preeclampsia and mostly are gone by 6 weeks after delivery. We have purified AT1-AA and have shown that they belong to the immunoglobulin (Ig)G3 subclass. We have shown their specificity by Western blotting, colocalization, and coimmunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappaBeta) activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. AT1-AA also signal via the calcineurin-nuclear factor of activated T cells and contribute to plasminogen activator inhibitor-1 (PAI-1) production and decreased trophoblast invasion. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proven with certainty. However, we believe the findings are compelling and warrant further study.

Agonistic AT(1) receptor autoantibodies and monocyte stimulation in hypertensive patients.

BACKGROUND: Agonistic AT(1) receptor autoantibodies (AT(1)-AA) have been described in hypertensive and preeclamptic patients. Furthermore, monocytes are activated in hypertensive patients. We investigated and compared the ability of angiotensin II (Ang II) and AT(1)-AA to stimulate monocytes from hypertensive and normotensive persons. The adhesiveness of the monocytes to endothelial cell layers, tissue factor expression, and chemiluminescence were determined. METHODS: Blood samples were obtained from 17 patients with essential hypertension and from 20 normotensive subjects. Peripheral blood monocytes were isolated by Dynabeads and used in adhesion experiments. Adherence assays, Western blotting, and reactive oxygen species release by chemiluminescence were done. RESULTS: Monocyte adhesion to human aortic or umbilical vein endothelial cell layers was significantly higher after stimulation with AT(1)-AA, compared to Ang II or no stimulation. The effect was blocked with tissue factor antibody or epitope peptide preincubation. Eposartan was partially effective in blocking the effects. Western blotting after AT(1)-AA or Ang II stimulation showed that the monocytes expressed tissue factor. The AT(1)-AA and Ang II induced significantly higher chemiluminescence in monocytes from hypertensive than control subjects. Endothelial cells, on the other hand, showed much less chemiluminescence. CONCLUSIONS: These data show that monocytes can be stimulated by AT(1)-AA and Ang II to adhere, produce tissue factor, and probably reactive oxygen species. They underscore the importance of monocyte activation in hypertensive patients. The relevance of AT(1)-AA in hypertension will require further studies.

Potential relevance of alpha(1)-adrenergic receptor autoantibodies in refractory hypertension.

BACKGROUND: Agonistic autoantibodies directed at the alpha(1)-adrenergic receptor (alpha(1)-AAB) have been described in patients with hypertension. We implied earlier that alpha(1)-AAB might have a mechanistic role and could represent a therapeutic target. METHODOLOGY/PRINCIPAL FINDINGS: To pursue the issue, we performed clinical and basic studies. We observed that 41 of 81 patients with refractory hypertension had alpha(1)-AAB; after immunoadsorption blood pressure was significantly reduced in these patients. Rabbits were immunized to generate alpha(1)-adrenergic receptor antibodies (alpha(1)-AB). Patient alpha(1)-AAB and rabbit alpha(1)-AB were purified using affinity chromatography and characterized both by epitope mapping and surface plasmon resonance measurements. Neonatal rat cardiomyocytes, rat vascular smooth muscle cells (VSMC), and Chinese hamster ovary cells transfected with the human alpha(1A)-adrenergic receptor were incubated with patient alpha(1)-AAB and rabbit alpha(1)-AB and the activation of signal transduction pathways was investigated by Western blot, confocal laser scanning microscopy, and gene expression. We found that phospholipase A2 group IIA (PLA2-IIA) and L-type calcium channel (Cacna1c) genes were upregulated in cardiomyocytes and VSMC after stimulation with both purified antibodies. We showed that patient alpha(1)-AAB and rabbit alpha(1)-AB result in protein kinase C alpha activation and transient extracellular-related kinase (EKR1/2) phosphorylation. Finally, we showed that the antibodies exert acute effects on intracellular Ca(2+) in cardiomyocytes and induce mesentery artery segment contraction. CONCLUSIONS/SIGNIFICANCE: Patient alpha(1)-AAB and rabbit alpha(1)-AB can induce signaling pathways important for hypertension and cardiac remodeling. Our data provide evidence for a potential clinical relevance for alpha(1)-AAB in hypertensive patients, and the notion of immunity as a possible cause of hypertension.

Agonistic antibodies directed at the angiotensin II, AT1 receptor in preeclampsia.

Immune mechanisms and circulating mediators may be important in the pathogenesis of preeclampsia. We review our findings on agonistic antibodies against the angiotensin II (Ang II) receptor (AT1-AA) and their possible role in the pathogenesis of this disorder. AT1-AA appear in the course of preeclampsia and are largely gone by 6 weeks after delivery. AT1-AA detection relies on a bioassay using spontaneously beating neonatal rat cardiomyocytes. Their specificity has been documented by other methods, including Western blotting, co-localization, and co-immunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including transcription factor activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proved with certainty. However, we believe the findings are compelling and warrant further study.

Agonistic autoantibodies directed against the angiotensin II AT1 receptor in patients with preeclampsia.

We showed that sera from patients with preeclampsia contain autoantibodies directed against the angiotensin II AT1 receptor. The antibodies recognize an epitope on the second extracellular loop of the receptor and are immunoglobulins of the IgG3 subclass. The antibodies accelerate the beating rate of neonatal rat cardiomyocytes. The agonistic effect can be blocked with the AT1 receptor blocker losartan and can be neutralized by a peptide corresponding to the AT1 receptor's second extracellular loop. In further studies we shown that the autoantibodies recognize a specific conformation of the AT1 receptor. Cleavage of the external disulfide bond with dithiothreitol caused an inactivation of the receptor when stimulated either with Ang II or the autoantibodies in a system of cultured neonatal rat cardiomyocytes. Long-term stimulation of the AT1 receptor with either agonists down-regulated the AT1 receptor-mediated response to a second Ang II stimulation. These observations show that the agonistic autoantibodies behave pharmacologically in a similar fashion to Ang II. We have found the autoantibodies in all women meeting the clinical criteria of preeclampsia and suggest that they may be important to the pathogenesis of the disease.

New aspects in the pathophysiology of preeclampsia.

Preeclampsia, the de novo occurrence of hypertension and proteinuria after the 20th week of gestation, continues to exert an inordinate toll on mothers and children alike. Recent clinical trials, new physiologic insights, and novel observations on pathogenesis have altered the thinking about preeclampsia. The mechanisms surrounding relaxin and its effects on the circulation and on matrix metalloproteinases have been elucidated. The growth factor's receptor, fms-like tyrosine kinase 1, has been shown to exist in a soluble form that is able to inactivate vascular endothelial-derived growth factor and human placental growth factor. Compelling evidence has been brought forth suggesting that fms-like tyrosine kinase 1 is a circulating factor that can cause preeclampsia. Preeclamptic women have high circulating levels of asymmetric dimethyl arginine that could account for the generalized endothelial dysfunction observed in preeclampsia. Preeclamptic women also produce novel autoantibodies that may serve to activate angiotensin receptors. These new observations raise the possibility that the treatment of preeclamptic women will soon be improved.