Endothelial Adhesion Molecules and Leukocyte Integrins in Preeclamptic Patients

Haller, Hermann; Ziegler, Eva-Maria; Homuth, Volker; Drab, Marek; Eichhorn, Jens; Nagy, Zsuzsanna; Busjahn, Andreas; Vetter, K.; Luft, Friedrich C.

doi:10.1161/01.hyp.29.1.291

Cited by 78 publications

(57 citation statements)

References 34 publications

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“…Impaired placentation and concomitant placental hypoxia induce the release of various factors in the maternal circulation that lead to enhanced endothelial permeability (25), altered expression of adhesion molecules, and increased intracellular free calcium content in the endothelium (26). VEGF is one of the most important growth and survival factors of endothelial cells, and free VEGF is reduced in the plasma of preeclamptic women (15), whereas its soluble receptor sFlt-1 is elevated in the serum of preeclamptic women (8).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D improves the angiogenic properties of endothelial progenitor cells

Grundmann

Haidar

Placzko

et al. 2012

American Journal of Physiology-Cell Physiology

137

113

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The main pathogenic feature of preeclampsia is maternal endothelial dysfunction that results from impaired angiogenesis and reduced endothelial repair capacity. In addition, preeclampsia risk is associated with vitamin D deficiency. We hypothesized that vitamin D3 stimulates proangiogenic properties of endothelial colony-forming cells (ECFCs). ECFCs were obtained and cultured from cord blood and characterized by immunocytochemistry and flow cytometry. Proliferation, total length of tubule formation on Matrigel, expression of VEGF mRNA, and pro-matrix metalloproteinases (MMP)-2 activity were assessed after treatment of ECFCs with vitamin D 3. Specificity of the observed effects was tested by blocking the vitamin D receptor (VDR) or the VEGF signaling pathway. ECFCs treated with 10 nM vitamin D3 showed a 1.27 times higher tubule formation compared with vehicle-treated controls (1.27 Ϯ 0.19) as well as a 1.36 times higher proliferation rate (1.36 Ϯ 0.06). Vitamin D3 induced pro-MMP-2 activity (1.29 Ϯ 0.17) and VEGF mRNA levels (1.74 Ϯ 0.73) in ECFCs. VDR blocking by pyridoxal-5-phosphate (0.73 Ϯ 0.19) or small interfering RNA (0.75 Ϯ 0.17) and VEGF inhibition by Su5416 (0.56 Ϯ 0.16) or soluble fms-like tyrosine kinase-1 (0.7 Ϯ 0.14) reduced tubule formation and pro-MMP-2 activity (pyridoxal-5-phosphate: 0.84 Ϯ 0.09; Su5416: 0.79 Ϯ 0.11; or sFlt: 0.88 Ϯ 0.13). This effect was neutralized by vitamin D3. Consequently, vitamin D3 significantly promoted angiogenesis in ECFCs in vitro possibly due to an increase in VEGF expression and pro-MMP-2 activity. Since angiogenesis is a crucial feature in the pathophysiology of preeclampsia these findings could explain the positive influence of vitamin D3 in reducing preeclampsia risk. vitamin D; preeclampsia; ECFC; angiogenesis; VEGF VITAMIN D, PRIMARILY KNOWN for its important role in calcium homeostasis and bone metabolism, influences the cardiovascular system through unclear mechanisms (33). Vitamin D deficiency is associated with increased all-cause and cardiovascular disease mortality, coronary heart disease, and various cardiovascular risk factors (33).Preeclampsia, a pregnancy-specific disorder that affects 3-7% of all pregnancies, is a major cause of maternal and fetal morbidity and mortality (43) and is associated with an increased risk for cardiovascular events later in life (6). Endothelial dysfunction underlies the hypertension, proteinuria, and multiorgan damage that occur during preeclampsia. The mechanisms that contribute to the disturbed endothelial homeostasis in the pathophysiology of preeclampsia remain unclear (41,46). Compared with normal pregnancies, preeclampsia is characterized by marked changes in vitamin D and calcium metabolism (3). Epidemiological studies have demonstrated an association between low maternal vitamin D levels and the incidence of preeclampsia (23, 27) and suggest vitamin D deficiency to be an independent risk factor for the development of preeclampsia (7). Moreover, vitamin D supplementation studies also showed protective effects on pr...

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Section: Discussionmentioning

confidence: 99%

Vitamin D improves the angiogenic properties of endothelial progenitor cells

Grundmann

Haidar

Placzko

et al. 2012

American Journal of Physiology-Cell Physiology

137

113

View full text Add to dashboard Cite

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“…Specific defects in resistance artery endothelium from women with preeclampsia have been shown (65). Supportive evidence for NO deficiency in preeclampsia has recently been obtained from the reduced uterine perfusion pressure rat model (66).…”

Section: Endothelium-derived Relaxing Factors and Their Inhibitorsmentioning

confidence: 90%

“…Haller et al (65,66) observed that a circulating factor in preeclamptic women caused endothelial cells to express surface adhesion molecules and made endothelial cell layers more permeable. The latter process involved the activation of protein kinase C. Wallukat et al (67) subsequently identified circulating autoantibodies that are capable of activating the angiotensin II (Ang II) AT1 receptor.…”

Section: Circulating Autoantibodiesmentioning

confidence: 99%

New Aspects in the Pathophysiology of Preeclampsia

Davison¹,

Homuth²,

Jeyabalan³

et al. 2004

Journal of the American Society of Nephrology

171

109

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Abstract. 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.The term preeclampsia refers to the new onset of hypertension (Ͼ140/90 mmHg) and proteinuria after 20 wk of gestation in previously normotensive, nonproteinuric women (1). The condition is common and occurs in~5% of pregnancies in the United States and Europe. Eclampsia is a life-threatening complication and is characterized by grand mal seizures. The term comes from the Greek word for lightning. A severe variant of preeclampsia also features hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). This condition occurs iñ 1 per 1000 pregnancies. Predisposing factors are a positive family history, hypertension, diabetes, preexisting renal disease, multiple pregnancies, and a poor obstetric history. Nephrologists are often called on to see preeclamptic women because of the severe BP elevation and renal disease. Thus, new clinical or experimental information on this condition is important information for nephrologists. Preeclampsia and Subsequent Cardiovascular RiskThe relevance of preeclampsia to the offspring is well recognized. Children who are born to preeclamptic mothers commonly have low birth weight, and their subsequent cardiovascular risk has been a vast investigational field. The mother's outcome has attracted less interest. Chesley, the father of modern preeclampsia research, was of the opinion that once the condition was over, the mothers had no greater risk of adverse long-term outcomes than women without preeclampsia from the general population (2). This issue may prove to be the only matter in which Chesley's opinion was erroneous. Several recent studies suggest that the converse is the case. Smith et al. (3) studied the pregnancy complications and the maternal risk of ischemic cardiac death in 129,290 births. They found that delivering an infant with low birth weight for gestational age increased the hazard ratio for ischemic heart disease o...

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“…10,11 Recently, we observed that circulating antibodies to a vascular receptor might be responsible for the hypertension observed in preeclampsia. 12 We found that the IgG fraction from preeclamptic women contains an angiotensin-1 receptor autoantibody (AT 1 -AA) that stimulates the AT 1 receptor.…”

Section: See Page 2335mentioning

confidence: 99%

“…10 Endogenous peroxidase was inactivated by immersing the sections in methanol containing 0.6% H 2 O 2 for 10 minutes. After the standard steps, the sections were developed in 3-amino-ethylcarbazole until a red/brown reaction product could be seen.…”

Section: Immunohistochemistrymentioning

confidence: 99%

AT ₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

et al. 2000

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Background-We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT 1 -AA) directed at the AT 1 receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT 1 -AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT 1 -AA cause vascular smooth muscle cells (VSMC) to express TF. Methods and Results-IgG from preeclamptic patients containing AT 1 -AA was purified with anti-human IgG columns.AT 1 -AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT 1 receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT 1 -AA specificity by coimmunoprecipitating the AT 1 receptor with AT 1 -AA but not with nonspecific IgG. Angiotensin (Ang) II and AT 1 -AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT 1 -AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect. Conclusions-We conclude that AT 1 -AA and Ang II both stimulate the AT 1 receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT 1 -AA on human cells that could contribute to the pathogenesis of preeclampsia.

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Endothelial Adhesion Molecules and Leukocyte Integrins in Preeclamptic Patients

Cited by 78 publications

References 34 publications

Vitamin D improves the angiogenic properties of endothelial progenitor cells

Vitamin D improves the angiogenic properties of endothelial progenitor cells

New Aspects in the Pathophysiology of Preeclampsia

AT ₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

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Endothelial Adhesion Molecules and Leukocyte Integrins in Preeclamptic Patients

Cited by 78 publications

References 34 publications

Vitamin D improves the angiogenic properties of endothelial progenitor cells

Vitamin D improves the angiogenic properties of endothelial progenitor cells

New Aspects in the Pathophysiology of Preeclampsia

AT 1 Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor

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Product

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AT ₁ Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor