Estudo de dois modelos de camundongos durante a gestação: I. Síndrome da Resposta Inflamatória Sistêmica x Nimesulida; II. Deficiência do Fator de Crescimento Placentário

Abstract

One of the most abundant immunologic cell types in early decidua is the uterine Natural Killer (uNK) cell that despite the presence of cytoplasmic granules rich in perforin and granzymes does not degranulate in normal pregnancy. UNK cells are important producers of angiogenic factors that permit normal dilation of uterine arteries to provide increased blood flow for the growing feto-placental unit. Gram-negative bacteria Lipopolysaccharide (LPS) administration can trigger cyclooxygenase-2 (COX-2) activation leading to an increase in prostaglandin level and an imbalance of pro-inflammatory and anti-inflammatory cytokines impairing the normal immune cells activity as well as uterine homeostasis. The present study aimed to evaluate if COX-2 inhibitor can alter the effect of LPS on the pregnant uterus, on blood vessels of the decidua, on uNK cells and on litter size; thus contributing to the elucidation of Systemic Inflammatory Syndrome mechanisms during pregnancy. The LPS administration caused excessive immature uNK cells influx in pregnant uterus as well as a decrease in mature uNK cells number concomitantly with altered uNK cells increasing. Such LPS effects could be prevented by the nimesulide pretreatment. The COX-2 inhibition has also prevented perforin releasing by these cells as well as the α-actin down-regulation in uterine blood vessels caused by LPS. The number of pups born from mothers treated with Nimesulide + LPS in mid-pregnancy was smaller than the number of pups born of mothers who received only LPS on the same gestation day. The injection of nimesulide itself showed no effect in the offspring, leading us to believe that the physiological changes after inflammation induced by LPS are of fundamental importance for the restoration of uterine homeostasis in order to maintain pregnancy to term.

Placental growth factor (PGF) is a pleiotropic angiogenic growth factor elevated during pregnancy. Although normal and abnormal patterns of maternal plasma PGF are well known, the precise roles of PGF in uteroplacental angiogenesis, blood pressure regulation, vasculogenesis, as well as cardiovascular (CV) and renal adaptation are undefined. Many women who express low levels of PGF over mid-pregnancy, progress to the acute, emergency, hypertensive syndrome of preeclampsia (PE). This kind of gestational complication elevate postpartum cardiovascular disease risks for both mothers and offspring. In many pre-eclamptic women, plasma placental growth factor concentrations are lower than normal, however, it is unknown if lower PGF elevates postpartum CV risk. We hypothesized that PGF deficiency limits maternal CV adaptations during mid-late pregnancy and contributes to postpartum maternal CV risk elevation. Cardiovascular function and structure were evaluated in Pgf^-/- and C57BL/6 (B6/Pgf^+/+) mice across pregnancy and postpartum. Furthermore, cerebral vascular structures were analyzed by polymer vascular casting technique and animals from both experimental groups were subjected to behavioral testing. Hemodynamic assessment by radiotelemetry showed Pgf^-/- x Pgf^-/- dams had a larger and more sustained mid-pregnancy decline in mean arterial pressure than controls but recovery post-transmitter implantation was rare. Hemodynamic assessment by tail cuff plethysmography showed that Pgf^-/- mice had higher blood pressure in early and late pregnancy with a longer interval of depressed systolic pressure after implantation. Lower maternal cardiac output and stroke volume were present after mid-gestation versus Pgf^+/+. Pgf^-/- left ventricular (LV) mass was less than in Pgf^+/+ and expected gestational increases in LV mass were observed only in Pgf^ +/+. Nos3 and Nos2 expression were elevated in midgestation Pgf^-/- LV. Structural anomalies were present in virgin Pgf^-/- glomeruli and renal hypertrophy was associated with gestation and postpartum. Thus, PGF deficiency limits physiological and structural adaptations of the mouse maternal CV and renal systems over late pregnancy. These results may have parallels in human pregnancy and relate to the postpartum gains in CV risk that are sequelae to pre-eclamptic gestations. Polymer vascular casting of offspring brains and behavioral testing revealed aberrant central vascular structure and major cognitive deficits in Pgf^-/-. Thus, gestational PGF deficiency additionally impairs regulation of maternal arterial pressure and vascular development in key organs of progeny such as the brain.