Increased vascular and uteroplacental matrix metalloproteinase-1 and -7 levels and collagen type I deposition in hypertension in pregnancy: role of TNF-α

Autor: Raouf A. Khalil, Wei Li, Ning Cui, Marc Q. Mazzuca, Karina M. Mata
Rok vydání: 2017
Předmět:
0301 basic medicine
medicine.medical_specialty
Physiology
Hypertension in Pregnancy
Placenta
Uterus
Ischemia
Blood Pressure
Gestational Age
030204 cardiovascular system & hematology
Matrix metalloproteinase
Biology
Vascular Remodeling
Collagen Type I
Preeclampsia
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Organ Culture Techniques
Pregnancy
Physiology (medical)
Internal medicine
medicine.artery
medicine
Animals
Placental Circulation
Aorta
Collagen type
Tumor Necrosis Factor-alpha
Editorial Focus
Hypertension
Pregnancy-Induced
medicine.disease
Placentation
Immunoglobulin Fc Fragments
Up-Regulation
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Matrix Metalloproteinase 7
Female
Matrix Metalloproteinase 1
Cardiology and Cardiovascular Medicine
Signal Transduction
Zdroj: American journal of physiology. Heart and circulatory physiology. 313(3)
ISSN: 1522-1539
Popis: 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. NEW & NOTEWORTHY The molecular mechanisms of preeclampsia are unclear, making it difficult to predict, prevent, or manage the pregnancy-associated disorder. This study showed that placental ischemia, possibly through the release of TNF-α, causes increases in the levels of matrix metalloproteinase (MMP)-1 and MMP-7, which could alter collagen deposition and cause inadequate uteroplacental and vascular remodeling in hypertension in pregnancy. The data suggest that targeting MMP-1 and MMP-7 and their upstream modulators, such as TNF-α, could provide a new approach in the management of hypertension in pregnancy and preeclampsia.
Databáze: OpenAIRE
Externí odkaz: