Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats

Younis, Husam S.; Jessen, Bart; Wu, Ellen; Stevens, Gregory J.

doi:10.1002/bdrb.20073

Cited by 10 publications

(6 citation statements)

References 44 publications

(53 reference statements)

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“…These observations are consistent with previous reports of decreased MMP levels in umbilical cord artery and microvascular endothelial cells of preeclamptic women [70, 71], and reduced levels/activity of MMP-2 and MMP-9 in the uterus, placenta and aorta of RUPP vs Preg rats [13, 41]. The data are also in accordance with reports that pharmacological inhibition of MMPs is associated with decreased placenta weight and cause IUGR in both normal Preg and HTN-Preg rats, and reduce trophoblast invasion and placental perfusion in HTN-Preg rats [72–74]. Importantly, in contrast with the increase in MMPs in the distal region of the Preg uterus, MMP-2 and MMP-9 were markedly decreased in the distal region of the RUPP uterus.…”

Section: Discussionsupporting

confidence: 86%

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Dias‐Junior

Chen

Cui

et al. 2017

Biochemical Pharmacology

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Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.

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Section: Discussionsupporting

confidence: 86%

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Dias‐Junior

Chen

Cui

et al. 2017

Biochemical Pharmacology

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“…cle cells are a major source of MMPs (83). These observations are in agreement with other reports that MMP levels are decreased in the umbilical cord artery and microvascular endothelial cells of PE women (25,26) and that pharmacological inhibition of MMPs is associated with decreased placenta weight and IUGR in both normal Preg and HTN-Preg rats and reduces trophoblast invasion and placental perfusion in HTN-Preg rats (66,78,97). In search for the cause of reduced MMPs during placental ischemia, the present study provides evidence that the decreases in MMP-2 and MMP-9 in RUPP rats are likely due to a sFlt-1/PlGF imbalance because infusing sFlt-1 in Preg rats caused decreases in MMP-2 and MMP-9 similar to those in RUPP rats, and infusing PlGF in RUPP rats restored MMP-2 and MMP-9 to the levels observed in control Preg rats.…”

Section: H40supporting

confidence: 87%

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

Ren

Cui

Zhu

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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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·day) in pregnant (Preg) rats increases blood pressure (BP) and alters MMPs and whether correcting sFlt-1/PlGF by infusing PlGF (20 µg·kg·day) 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.

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“…However, they did not evaluate the effect of doxycycline on the development of pregnancy-induced hypertension [134]. Although, previous studies have also reported adverse effects of MMP inhibitors on pregnant animals [135–138], such effects were not reported by others [139–141]. Indeed, doxycycline is the only MMP inhibitor currently approved by the U.S. Food and Drug Administration (FDA) [142] and, when prescribed as an antibiotic during pregnancy, it is classified as a potentially teratogenic medication (class D: potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks) [143].…”

Section: Evidence Supporting the Use Of Mmp Inhibitors In Preeclammentioning

confidence: 99%

Matrix Metalloproteinases as Drug Targets in Preeclampsia

Palei

Granger²,

Tanus‐Santos

2013

CDT

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Preeclampsia is an important syndrome complicating pregnancy. While the pathogenesis of preeclampsia is not entirely known, poor placental perfusion leading to widespread maternal endothelial dysfunction is accepted as a major mechanism. It has been suggested that altered placental expression of matrix metalloproteinases (MMPs) may cause shallow cytotrophoblastic invasion and incomplete remodeling of the spiral arteries. MMPs are also thought to link placental ischemia to the cardiovascular alterations of preeclampsia. In fact, MMPs may promote vasoconstriction and surface receptors cleavage affecting the vasculature. Therefore, the overall goal of this review article is to provide an overview of the pathophisiology of preeclampsia, more specifically regarding the role of MMPs in the pathogenesis of preeclampsia and the potential of MMP inhibitors as therapeutic options.

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Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats

Abstract: These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.

Cited by 10 publications

References 44 publications

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

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

Matrix Metalloproteinases as Drug Targets in Preeclampsia

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