Objective An animal model of hemolysis, elevated liver enzymes, low platelet count (HELLP) was used to determine if T lymphocytes accompany hypertension and increased inflammatory cytokines. Methods sFlt-1 (4.7 μg/kg/day) and sEndoglin (7 μg/kg/day) were infused into normal pregnant rats (HELLP rats) for 8 days. Results HELLP was associated with increased mean arterial pressure (p = 0.0001), hemolysis (p = 0.044), elevated liver enzymes (p = 0.027), and reduced platelets (p = 0.035). HELLP rats had increased plasma levels of TNFα (p = 0.039), IL-6 (p = 0.038) and IL-17 (p = 0.04). CD4+ and CD8+ T lymphocytes were increased. Conclusion These data support the hypothesis that T cells are associated with hypertension and inflammation.
Preeclampsia is associated with oxidative stress which is suspected to play a role in hypertension, placental ischemia and fetal demise associated with the disease. Various cellular sources of oxidative stress such as neutrophils, monocytes and CD4+T cells have been suggested as culprits in the pathophysiology of preeclampsia. The objective of this study was to examine a role for circulating and placental CD4+T cells in oxidative stress in response to placental ischemia during pregnancy. CD4+T cells and oxidative stress was measured in preeclamptic and normal pregnant women, placental ischemic and normal pregnant rats and normal pregnant recipient rats of placental ischemic CD4+ T cells. Preeclamptic women had significantly increased circulating (p=0.02) and placental CD4+T cells (p=0.0001); lymphocyte secretion of myeloperoxidase (p=0.004); and placental reactive oxygen species (p=0.0004) compared to normal pregnant women. CD4+T cells from placental ischemic rats cause many facets of preeclampsia when injected into normal pregnant recipient rats on gestational day 13. On gestational day 19 blood pressure increased in normal pregnant recipients of placental ischemic CD4+T cells (p=0.002) compared to normal pregnant rats. Similar to preeclamptic patients, CD4+ T cells from placental ischemic rats secreted significantly more myeloperoxidase (p=0.003) and induced oxidative stress in cultured vascular cells (p=0.003) than normal pregnant rat CD4+Tcells. Apocynin, an NADPH inhibitor, attenuated hypertension, and all oxidative stress markers in placental ischemic and normal pregnant recipient rats of placental ischemic CD4+Tcells (p=0.05). These data demonstrate an important role for CD4+T cells in mediating another factor, oxidative stress, to cause hypertension during preeclampsia.
Objective: To determine a role for endothelin (ET) in progression of uterine fibroids. Design: An in vitro model of fibroid and myometrium cultivation. Patients: A total of 32 women undergoing hysterectomies for uterine fibroids and 11 women undergoing hysterectomies for abnormal uterine bleeding (control population). Results: Women with uterine fibroids were hypertensive and displayed significantly greater circulating ET-1 compared to control patients. Secretion of ET-1 was greater from the fibroids compared to myometrium explants. Endothelin 1 secretion was attenuated with blockade of the angiotensin II type 1 or endothelin A receptors. Hypoxia stimulated ET-1 secretion from both myometrium and fibroid explants. Preproendothelin messenger RNA expression increased with hypoxia from fibroid explants compared to normoxic controls. Conclusions: These data support the hypothesis that uterine fibroids are associated with hypertension and increased ET-1, which is exacerbated with hypoxia. These data suggest a possible link between mechanisms of blood pressure regulation and development of uterine leiomyoma.
Cysteine-rich angiogenic inducer 61 (CYR61), an angiogenic factor whose expression is decreased in fibroids. The aim of the present study was to determine if CYR61 secretion in smooth muscle cells (SMCs) is regulated by hypoxia and through the endothelin A (ETA) receptor. SMCs from fibroids (fSMC) and the adjacent myometrium smooth muscle cells (mSMCs) were extracted from ten women undergoing hysterectomy for uterine fibroids and cultured with or without 1.0 μM of an ETA receptor antagonist for 24 h under either normal or hypoxic oxygen conditions. Cellular secretion of endothelin-1 (ET-1) and CYR61 were measured via enzyme linked immunosorbent assay in the cell culture media. SMCs were collected to determine cell proliferation and CYR61 protein expression via Western blot. ET-1 secretion was significantly increased in fSMC and was decreased with blockade of the ETA receptor under both normoxia (P=0.0004) and hypoxia (P=0.008). CYR61 expression was decreased in fSMCs and significantly increased with blockade of the ETA receptor under hypoxia (P=0.04). Cell proliferation decreased with ETA blockade under normoxia (P=0.0001) and hypoxia (P=0.001). These results suggest that suppression of CYR61 secretion in fSMC is regulated by the ET-1 and that blockade with ETA could be considered for a future treatment option.
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