angiotensinogen and Thrombosis

Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin-angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin-angiotensin system blockers, and is compatible with the possibility that blocking local renin-angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Endothelium, Vascular; Humans; Hypertension; Renin; Renin-Angiotensin System; Risk Factors; Thromboplastin; Thrombosis

Discriminant analysis (DA) was performed on data of two combined hormonal contraceptives (CHC) differing in estrogen ratio to explore whether a combination of variables rather than a single variable distinguishes CHCs better.. Data were used of a parallel study in premenopausal women treated for three cycles (21 days on, 7 days off) with a contraceptive vaginal ring delivering Nestorone and ethinyl estradiol (EE) or an oral contraceptive containing levonorgestrel and EE. DA was performed on the change from baseline (CFB) and the end-of-treatment values at 3 months for lipids, sex-hormone binding globulin (SHBG), C-reactive protein, angiotensinogen, blood pressure and hemostasis variables, and on the hemostasis variables only.. For the complete set, the CFB for factor VII (FVII), SHBG and plasminogen (PLG), or end-of-treatment SHBG- and FVII level discriminated the treatments best. Maximal discrimination for the hemostasis data was by CFB for FVII and PLG or end-of-treatment FVII level.. DA identifies differences between CHCs and may provide information on the factors associated with thrombotic risk.

Topics: Angiotensinogen; Blood Coagulation Factors; Blood Pressure; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Contraceptive Devices, Female; Contraceptives, Oral, Combined; Discriminant Analysis; Drug Combinations; Ethinyl Estradiol; Female; Humans; Levonorgestrel; Norprogesterones; Risk; Sex Hormone-Binding Globulin; Thrombosis; Triglycerides

Maternal spiral artery remodeling is the consequence of controlled trophoblast invasive interaction with the maternal cellular environment and is fundamentally important for successful placentation. In preeclampsia, trophoblast invasion is shallow, remodeling is incomplete, and vessels develop an inflammatory appearance, termed "acute atherosis." We noted that, in our preeclampsia, human renin-human angiotensinogen transgenic rat model, complement component 3 (C3), and tumor necrosis factor-alpha were upregulated and heavily expressed in atherotic uteroplacental vessels. We next used coculture involving human trophoblasts, rat vascular smooth muscle cells (VSMCs), and human VSMCs to observe VSMC-trophoblast regulatory interactions. Tumor necrosis factor-alpha induced complement C3 and interleukin-6 expression in VSMCs. We found that trophoblasts were able to reduce VSMC C3 and interleukin-6 expression after the VSMCs were stimulated with tumor necrosis factor-alpha. However, a direct VSMC-trophoblast cell-cell contact was necessary for this anti-inflammatory response. We also studied double-transgenic VSMCs that express inflammatory components and exhibit accelerated proliferation ("synthetic" phenotype). Trophoblasts could not downregulate C3 in these cells. We then examined uteroplacental tissues from preeclamptic and control patients. In control deciduas, only traces of C3 staining were observed, and vessels were thin walled without thrombus formation. In preeclampsia, the decidual vessels showed atherosis, thrombus formation, and C3 expression. Our data suggest that fetally derived trophoblasts require direct cell-cell contact with maternally derived VSMCs to downregulate VSMC C3 and interleukin-6 expression and to avoid atherosis. The findings also implicate C3 in the placental vasculopathy observed in preeclampsia.

Topics: Acute Disease; Angiotensinogen; Animals; Animals, Genetically Modified; Atherosclerosis; Cell Communication; Cells, Cultured; Chorionic Villi; Coculture Techniques; Complement C3; Decidua; Female; Humans; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Renin; Thrombosis; Trophoblasts