Altered matrix metalloproteinase-2 and -9 expression/activity links placental ischemia and anti-angiogenic sFlt-1 to uteroplacental and vascular remodeling and collagen deposition in hypertensive pregnancy

Li, Wei; Mata, Karina M.; Mazzuca, M; Khalil, Raouf A.

doi:10.1016/j.bcp.2014.03.017

Cited by 82 publications

(123 citation statements)

References 73 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…A study has shown that both serum MMP-2 and TIMP-1 levels are increased in PE [67], while other studies suggest that decreased levels of MMP-2 in UCA reduce the breakdown of collagen in the arterial wall [2]. Other studies have shown changes in MMP-2 and −9 protein amount and activity in uterine, placental and aortic tissue of RUPP rats [68]. MMPs may have a bi-directional relationship with VEGF, whereby VEGF upregulates MMP expression, while membrane type-1 MMP promotes VEGF expression [2].…”

Section: Extracellular Matrix and Matrix Metalloproteinases In Pementioning

confidence: 99%

Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy

Ali

Khalil

2015

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

Introduction Preeclampsia (PE) is a major complication of pregnancy that could lead to maternal and fetal morbidity and mortality. The pathophysiological mechanisms of PE are not completely understood, but recent research has begun to unravel some of the potential mechanisms. Areas covered Genetic polymorphisms and altered maternal immune response may cause impaired remodeling of the spiral arteries; a potential early defect in PE. Inadequate invasion of cytotrophoblasts into the decidua leads to reduced uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia. Placental ischemia causes the release of biologically active factors such as anti-angiogenic factors, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and angiotensin II receptor autoantibodies. These vasoactive factors could cause systemic vascular endotheliosis and consequent increase in vascular resistance and blood pressure, glomerular endotheliosis causing proteinuria, cerebrovascular endotheliosis causing cerebral edema, seizures and visual disturbances, and hepatic endotheliosis which may contribute to the manifestations of HELLP syndrome. PE-associated vascular endotheliosis causes a decrease in vasodilator mediators such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor, an increase in vasoconstrictors such as endothelin-1, angiotensin II and thromboxane A2, and enhanced mechanisms of vascular smooth muscle contraction such as intracellular Ca2+, protein kinase C and Rho-kinase. Changes in matrix metalloproteinase activity and extracellular matrix cause vascular remodeling and further vasoconstriction. Expert opinion Some of the genetic, immune and vasoactive factors involved in vascular endotheliosis could be used as biomarkers for early detection, and as potential targets for prevention and treatment of PE.

show abstract

Section: Extracellular Matrix and Matrix Metalloproteinases In Pementioning

confidence: 99%

Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy

Ali

Khalil

2015

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…Images of the aorta, carotid artery, mesenteric artery, and renal artery were acquired using bright-field and ϫ40 objectives, and images of the virgin uterus were acquired with a ϫ4 objective. Because the rat pregnant uterus is large, 20 picture frames of sequential parts of the uterine wall were acquired using the ϫ4 objective, and the composite image of the whole uterine section was reconstituted as previously described (39). Images were analyzed using ImageJ, the total number of pixels in the tissue section image was defined, and the number of brown spots (pixels) was counted and then presented as a percentage of total pixels.…”

Section: Methodsmentioning

confidence: 99%

“…Images of arteries were acquired using bright-field and ϫ4 and ϫ40 objectives. Because the rat uterus is large, 20 picture frames of sequential parts of the uterine tissue section were acquired using the ϫ4 objective, and the composite image of the whole uterine section was reconstituted as previously described (39). Images of tissue sections were analyzed using ImageJ.…”

Section: Methodsmentioning

confidence: 99%

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Mata

Reslan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

RA. Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy. Am J Physiol Heart Circ Physiol 309: H1679 -H1696, 2015. First published September 25, 2015 doi:10.1152/ajpheart.00532.2015.-Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E 2) may promote vasodilation during pregnancy; however, the specific E 2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/ distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E 2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ER␣, ER␤, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E 2 (all ERs) and the specific ER agonist 4,4=,4Љ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ER␣), diarylpropionitrile (DPN; ER␤), and G1 (GPER). BP was slightly lower and plasma E 2 was higher in pregnant versus virgin rats. Western blots revealed increased ER␣ and ER␤ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrineprecontracted vessels, E 2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN-and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E 2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E 2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E 2, PPT, DPN, and G1 caused relaxation of Ca 2ϩ entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ER␣ expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ER␣-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca 2ϩ entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ER␣ in pregnancyassociated vasodilation. GPER may contribute to aortic relaxation while enhanced ER␤ expression could mediate other genomic vascular effects during pregnancy.

show abstract

“…MMP-2 degrades collagen I, II, III, IV, V, VII, X and XI while MMP-9 degrades collagen IV, V, VII, X and XIV. With low MMP levels, excessive collagen deposition may affect smooth muscle growth and decrease spiral arteries remodeling [77]. …”

Section: Introductionmentioning

confidence: 99%

Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia

Shah

Khalil

2015

Biochemical Pharmacology

Self Cite

151

124

View full text Add to dashboard Cite

Preeclampsia is a pregnancy-associated disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality; however, the pathophysiological mechanisms involved are unclear. Predisposing demographic, genetic and environmental risk factors could cause localized abnormalities in uteroplacental cytoactive factors such as integrins, matrix metalloproteinases, cytokines and major histocompatibility complex molecules leading to decreased vascular remodeling, uteroplacental vasoconstriction, trophoblast cells apoptosis, and abnormal development of the placenta. Defective placentation and decreased trophoblast invasion of the myometrium cause reduction in uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia, an important event in preeclampsia. RUPP could stimulate the release of circulating bioactive factors such as the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin that cause imbalance with the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or cause the release of inflammatory cytokines, reactive oxygen species, hypoxia-induced factor-1 and AT1 angiotensin receptor agonistic autoantibodies. The circulating bioactive factors target endothelial cells causing generalized endotheliosis, endothelial dysfunction, decreased vasodilators such as nitric oxide and prostacyclin and increased vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction. The bioactive factors also stimulate the mechanisms of VSM contraction including Ca2+, protein kinase C, and Rho-kinase and induce extracellular matrix remodeling leading to further vasoconstriction and hypertension. While therapeutic options are currently limited, understanding the underlying mechanisms could help design new interventions for management of preeclampsia.

show abstract

Altered matrix metalloproteinase-2 and -9 expression/activity links placental ischemia and anti-angiogenic sFlt-1 to uteroplacental and vascular remodeling and collagen deposition in hypertensive pregnancy

Cited by 82 publications

References 73 publications

Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy

Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia

Contact Info

Product

Resources

About