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Role Of Neutrophils In Enhancing Vascular Reactivity To Angiotensin Ii In Preeclampsia, Nikita Mishra
Role Of Neutrophils In Enhancing Vascular Reactivity To Angiotensin Ii In Preeclampsia, Nikita Mishra
Theses and Dissertations
Women with preeclampsia have enhanced vascular reactivity to Angiotensin II (Ang II) and extensive vascular infiltration of neutrophils. The primary mechanism to enhance vessel reactivity is RhoA kinase that phosphorylates MYPT1 to inhibit myosin light chain (MLC) phosphatase. Therefore, MLCs remain phosphorylated and increase sensitivity to calcium. Neutrophils release reactive oxygen species (ROS), which can activate this pathway, so we hypothesized that neutrophils would enhance vessel reactivity to Ang II. Omental vessels from normal pregnant women were used to study vascular reactivity. Ang II dose response (0.001-10µM) was significantly enhanced with perfusion of neutrophils (<2000/mm3, activated with IL-8) or ROS. Addition of superoxide dismutase (SOD)/Catalase to quench ROS or 3µM Y-27632, a specific RhoA kinase inhibitor, blocked enhancement. Vascular smooth muscle expression of pMYPT1 and pMLC in cell culture was significantly increased by neutrophils or ROS. The increase was prevented by Y-27632. RhoA kinase activity assay showed a 3-fold increase in RhoA kinase activity in omental vessels treated with ROS. Similarly, ROS also enhanced vessel reactivity to another vasoconstrictor, norepinephrine, via RhoA kinase. In preeclamptic women, increased neutrophil infiltration is associated with increased vascular expression and production of matrix metalloproteinase-1 (MMP-1). MMP-1 activates protease activated receptor-1 (PAR-1), which could cause endothelial endothelin-1 release, so we considered a novel hypothesis that MMP-1 might cause vasoconstriction and enhance vessel reactivity to Ang II via PAR-1. Omental vessels perfused with activated MMP-1 (0.025-25ng/ml) showed dose-dependent vasoconstriction. Perfusion of activated MMP-1 (2.5ng/ml) significantly enhanced dose response to angiotensin II. MMP-1 mediated vasoconstriction and enhanced vessel reactivity to Ang II was abolished by co-perfusion of 10µM SCH-79797, a specific PAR-1 blocker, and by 5µM BQ-123, a specific endothelin-1 type A receptor blocker. These data are the first to show that activated neutrophils enhance vascular reactivity to Ang II via ROS and the RhoA kinase pathway. They are also the first to show that MMP-1 induces vasoconstriction and enhances vessel reactivity to Ang II. Thus, vascular neutrophil infiltration leading to ROS and MMP-1 generation could be an important mechanism for hypertension in preeclampsia.
Neutrophil Products Control The Expression Of Progesterone Receptors And Matrix Metalloproteinase-1 In The Decidual And Myometrium And Are Possible Regulators Of Premature Labor, Anna Solotskaya
Theses and Dissertations
Neutrophils infiltrate myometrium and decidual tissue prior to parturition. Activated neutrophils release reactive oxygen species (ROS) and tumor necrosis factor α (TNFα), which might increase expression of pro-labor genes such as matrix metalloproteinase-1 (MMP-1), progesterone receptor (PR) A/B ratio, and cause demethylation of DNA. These changes might cause labor. Decidual tissue was obtained from consented, healthy women at term (37+ weeks of gestation) not in labor (no contractions, without cervical effacement), term labor and preterm labor (under 37 weeks of pregnancy). Decidual and myometrial cells in culture were treated with (1) ROS, (2) TNFα, or (3) 5-aza-2’-deoxycytidine. Total RNA was …