Preeclampsia is characterized by development of hypertension during pregnancy and reduced placental perfusion. Previous studies in a rat model of placental ischemia-induced hypertension demonstrated that inhibiting complement activation attenuated increased maternal blood pressure with C3a and C5a identified as the important products of complement activation. Given that in other forms of ischemia both natural IgM and antigen antibody complexes initiate complement activation, we hypothesized that placental ischemia exposes neoepitopes recognized by IgM to cause local complement activation and hypertension. Alternatively, we postulated that autoantibody to angiotensin II Type 1 receptor (AT1-AA) interacts with AT1 receptors to cause complement activation. Since complement activation occurs in kidney and placenta in preeclampsia, we used immunohistochemistry to determine IgM deposition and local complement activation in each organ (C3 deposition), and quantitative real-time polymerase chain reaction (qRT-PCR) to quantitate mRNA for endogenous regulators of complement activation CD55, CD59 and Complement receptor 1-related gene/protein y (Crry). On gestation day (GD)14.5, timed pregnant Sprague Dawley rats underwent Sham surgery or placement of clips on inferior abdominal aorta and ovarian arteries to create placental ischemia using the reduced utero-placental perfusion pressure (RUPP) model. As previously reported, RUPP surgery increased mean arterial pressure and circulating C3a on GD19.5. In placenta, IgM and C3 deposition increased, whereas mRNA for complement regulators Crry and CD59 decreased along with Crry protein in RUPP compared to Sham treated animals. In kidney, IgM deposition increased in animals subjected to RUPP vs Sham surgery without a significant change in C3 deposition and coincident with an increase in mRNA for CD55 and CD59. The AT1 receptor antagonist losartan prevents placental ischemia-induced hypertension as well as AT1-AA interaction with AT1 receptors. However, losartan did not attenuate complement activation as measured by circulating C3a or placental C3 deposition. Importantly, our studies indicate that following placental ischemia, complement activation is not due to AT1-AA but is associated with IgM deposition. These studies suggest a role for natural antibodies interacting with placental ischemia-induced neoepitopes to activate complement and contribute to hypertension.
Early onset preeclampsia is characterized by hypertension, reduced placental perfusion, intrauterine growth restriction and increased activation of complement, part of innate immunity. We previously reported that inhibiting complement activation attenuates reduced uterine perfusion pressure (RUPP)-induced hypertension in pregnant rat and the concomitant increase in complement activation product C3a. Studies by other groups indicate endothelin A receptor (ET A ) activation plays a significant role in RUPP-induced hypertension. We hypothesized that ET A was important in placental ischemia-induced complement activation leading to hypertension. Thus, the effect of ET A antagonist atrasentan on hypertension and complement activation following placental ischemia in rat was determined. Dams received drinking water with or without 5 mg/kg/day atrasentan on gestation day (GD)13-19. On GD14, rats underwent Sham or RUPP surgery with clip placement on abdominal aorta and uterine arteries to decrease placental perfusion. On GD19, mean arterial pressure (MAP) via arterial catheter and serum C3a as indicator of complement activation were measured. RUPP surgery significantly increased MAP (109±5 mm Hg; n=7) compared to Sham (94±4 mm Hg; n=10) as well as C3a (0.36±0.08 to 0.69±0.12 units/ul). MAP was significantly reduced by atrasentan in RUPP (96±3 mm Hg; n=12) and unchanged by atrasentan in Sham (88±2 mm Hg; n=12). RUPP did not change preproendothelin mRNA in kidney cortex versus Sham, but did decrease fetal weight. In Sham, atrasentan significantly increased fetal weight (2.52±0.04 g; n=12) compared to no atrasentan (2.38±0.05 g; n=12). Importantly, atrasentan treatment did not significantly change RUPP-induced increase in C3a with 0.57±0.11 units/ul in RUPP atrasentan and 0.27±0.05 units/ul in Sham atrasentan. In contrast to other ET A antagonists (A-127722, FR-139317), the present data indicate atrasentan may promote fetal growth. However, the ET A receptor does not mediate increased complement activation and its subsequent involvement in placental ischemia-induced hypertension. Thus, our data suggest complement activation may precede involvement of endothelin in development and maintenance of high blood pressure due to placental ischemia.
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