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Preeclampsia is a complication of pregnancy manifested as maternal hypertension (HTN) and fetal intrauterine growth restriction, with unclear mechanisms. Placental ischemia increases antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) relative to angiogenic placental growth factor (PlGF); however, the molecular targets are unclear. To test the hypothesis that placental ischemia-induced changes in sFlt-1 and PlGF target vascular and uteroplacental matrix metalloproteinases (MMPs), we tested whether raising the sFlt-1-to-PlGF ratio by infusing sFlt-1 (10 µg·kg−1·day−1) in pregnant (Preg) rats increases blood pressure (BP) and alters MMPs and whether correcting sFlt-1/PlGF by infusing PlGF (20 µg·kg−1·day−1) in Preg rats with reduced uterine perfusion pressure (RUPP) improves BP and reverses the changes in MMPs. On gestational day 19, BP was higher and the litter size and uterine, placenta, and pup weight were less in Preg + sFlt-1 and RUPP than Preg rats and restored in RUPP + PlGF versus RUPP rats. Gelatin and casein zymography and Western blots revealed decreases in MMP-2 and MMP-9 and increases in MMP-1 and MMP-7 in the aorta, uterine artery, uterus, and placenta of Preg + sFlt-1 and RUPP versus Preg rats, which were reversed in RUPP + PlGF versus RUPP rats. Collagen types I and IV were more abundant in Preg + sFlt-1 and RUPP versus Preg rats and were reversed in RUPP + PlGF versus RUPP rats. Thus, PlGF reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and sFlt-1 in HTN in pregnancy. Angiogenic factors and MMP modulators could rectify changes in MMPs and collagen, restore vascular and uteroplacental remodeling, and improve HTN and intrauterine growth restriction in preeclampsia.
NEW & NOTEWORTHY Understanding the mechanisms of preeclampsia could help in its prevention and management. This study shows that correcting soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) imbalance by infusing PlGF reverses the decreases in vascular and uteroplacental matrix metalloproteinase (MMP)-2 and MMP-9 and the increases in MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and antiangiogenic sFlt-1 in hypertension in pregnancy. Angiogenic factors and MMP modulators could rectify changes in vascular and uteroplacental MMPs and collagen content and ameliorate hypertension and intrauterine growth restriction in preeclampsia.
aorta, hypertension, myometrium, placenta, preeclampsia, remodeling, uterine artery
Placental growth factor reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1 and MMP-7 and collagen types I and IV in hypertensive pregnancy
Zongli Ren, Ning Cui, Minglin Zhu, and Raouf A. Khalilcorresponding author
2018 Jul 1
Preeclampsia is a pregnancy-related disorder manifested as maternal hypertension in pregnancy (HTN-Preg) and fetal growth restriction. Placental ischemia could be an initiating event that leads to abnormal vascular and uteroplacental remodeling in HTN-Preg; however, the molecular targets and intermediary mechanisms involved are unclear. We tested the hypothesis that placental ischemia could target vascular and uteroplacental matrix metalloproteinases (MMPs) through an inflammatory cytokine-mediated mechanism. MMP levels and distribution were measured in the aorta, uterus, and placenta of normal pregnant (Preg) rats and pregnant rats with reduced uterine perfusion pressure (RUPP). Maternal blood pressure was higher and the litter size and pup weight were lower in RUPP compared with Preg rats. Gelatin zymography showed prominent uterine MMP-2 and MMP-9 activity that was dependent on the amount of loaded protein. At saturating protein loading, both gelatin and casein zymography revealed two additional bands corresponding to MMP-1 and MMP-7 that were greater in the aorta, uterus, and placenta of RUPP compared with Preg rats. Western blots and immunohistochemistry confirmed increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of RUPP versus Preg rats. The levels of MMP-1 and MMP-7 substrate collagen type I were greater in tissues of RUPP compared with Preg rats. In organ culture, TNF-α increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of Preg rats, and a TNF-α antagonist prevented the increases in MMPs in tissues of RUPP rats. Thus, placental ischemia, possibly through TNF-α, increases vascular and uteroplacental MMP-1 and MMP-7, which, in turn, alter collagen deposition and cause inadequate tissue remodeling in HTN-Preg. Cytokine antagonists may reverse the increase in MMP-1 and MMP-7 expression/activity and, in turn, restore proper vascular and uteroplacental remodeling in HTN-Preg and preeclampsia.
aorta, placenta, preeclampsia, remodeling, uterus, tumor necrosis factor-α
Increased vascular and uteroplacental matrix metalloproteinase-1 and -7 levels and collagen type I deposition in hypertension in pregnancy: role of TNF-α
Wei Li, Ning Cui, Marc Q. Mazzuca, Karina M. Mata, and Raouf A. Khalilcorresponding author
2017 Sep 1;
This study aims to describe trends in the prevalence of depression among hospitalized patients with type 2 diabetes in Spain, 2001-2011.
We selected patients with a discharge diagnosis of type 2 diabetes using national hospital discharge data. Discharges were grouped by depression status. Prevalence of depression globally and according to primary diagnoses based on the Charlson comorbidity index (CCI) were analyzed. We calculated length of stay (LOHS) and in-hospital mortality (IHM). Multivariate analysis was adjusted by age, year and comorbidity.
From 2001 to 2011, 4,723,338 discharges with type 2 diabetes were identified (4.93% with depression). Prevalence of depression in diabetic patients increased from 3.54% in 2001 to 5.80% in 2011 (p<0.05). The prevalence of depression was significantly higher in women than in men in each year studied and increased from 5.22% in 2001 to 9.24% in 2011 (p<0.01). The highest prevalence was observed in the youngest age group (35-59 years). The median LOHS decreased significantly over this period. Men with diabetes and depression had higher IHM than women in all the years studied (p<0.05). Older age and greater comorbidity were significantly associated with a higher risk of dying, among diabetic patients with concomitant depression. Conclusions Prevalence of depression increased significantly among hospitalized diabetic patients from 2001 to 2011 even if the health profile and LOHS have improved over this period. Programs targeted at preventing depression among persons with diabetes should be reinforced in Spain.
Trends in the Prevalence of Depression in Hospitalized Patients with Type 2 Diabetes in Spain: Analysis of Hospital Discharge Data from 2001 to 2011
Ana Lopez-de-Andres, 1 ,* Mª Isabel Jimenez-Trujillo, 1 Valentin Hernandez-Barrera, 1 Jose Mª de Miguel-Yanes, 2 Manuel Mendez-Bailon, 3 Napoleon Perez-Farinos, 4 Carmen de Burgos Lunar, 5 Juan Cardenas-Valladolid, 6 Miguel angel Salinero-Fort, 6 Rodrigo Jimenez-Garcia, 1 and Pilar Carrasco-Garrido 1