Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.

Li, X; Shams, M.; Zhu, Jianmeng; Khalig, A; Wilkes, Mark C.; Whittle, Martin; Barnes, NM; Ahmed, Asif

doi:10.1172/jci119881

Cited by 108 publications

(87 citation statements)

References 47 publications

(48 reference statements)

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“…There was no difference in AT 2 receptor density between normal and preeclamptic tissues consistent with several previously studies. 22,41,44 In addition, mRNA levels of the Mas receptor, a reported Ang-(1-7) receptor, 45 were lower in preeclamptic than normal chorionic villi. Low levels of the Mas receptor were also observed with the measurement of AT 1-7 receptor density by autoradiography; however, there was no difference in the density between normal and preeclamptic chorionic villi.…”

Section: Discussionmentioning

confidence: 99%

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

et al. 2008

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Abstract-The chorionic villi in the placenta are responsible for the regulation of fetal oxygen and nutrient transport.Although the peripheral renin-angiotensin system is activated during normal pregnancy, the regulation of the local chorionic villi renin-angiotensin system remains unknown. Therefore, placental chorionic villous tissue was collected from nulliparous third-trimester normotensive or preeclamptic subjects and was analyzed for angiotensin peptide content, angiotensinogen, renin, angiotensin-converting enzyme (ACE), ACE2, neprilysin, angiotensin II type 1 (AT 1 ), angiotensin II type 2, Mas receptor mRNAs, and angiotensin receptor density and subtype. Angiotensin II in chorionic villi was significantly higher in preeclamptic subjects, whereas angiotensin (1-7) was not different. Key Words: preeclampsia Ⅲ renin angiotensin system Ⅲ pregnancy Ⅲ placenta Ⅲ angiotensin receptors Ⅲ Mas receptor Ⅲ angiotensin (1-7) P reeclampsia, a hypertensive disorder of pregnancy, is clinically defined as maternal hypertension, proteinuria, and generalized edema occurring after the 20th week of gestation. Preeclampsia is the second leading cause of maternal mortality in the United States, affecting 7% to 10% of all pregnancies and contributing significantly to stillbirths and neonatal morbidity and mortality. 1 Thus, the prevention of preeclampsia would have a significant impact on maternal and neonatal outcome. Nevertheless, the pathophysiology of preeclampsia remains poorly understood. Although preeclampsia is often considered a multisystem disorder, one of the postulated pathological features of this disease is an impaired maternal uterine spiral artery remodeling. In preeclampsia, there is a decrease of embryonic trophoblast cell invasion of the uterine spiral arteries, which, in turn, prevents the diameter of these arteries from expanding and consequently leads to a reduction of blood flow into the placenta. 2,3 Without the remodeling of the uterine vasculature, the placenta becomes hypoxic as gestation advances, resulting in an oxygen deficiency within the tissue. The hypoxic placenta can then release factors into the maternal circulation that result in generalized endothelial dysfunction, vascular inflammation, and proteinuria. [3][4][5] Although several factors, including soluble fms-like tyrosine kinase 1 6 and soluble endoglin, 7 were discovered recently to play a role in the pathogenesis of preeclampsia, there are still many unanswered questions in the development of this disease.The renin-angiotensin system (RAS) is an important regulator of blood pressure, sodium, and fluid homeostasis and has been shown previously to play a role in preeclampsia. In normal pregnancy, estrogen causes an overexpression of the RAS by increasing both tissue and circulating levels of angiotensinogen 8,9 and renin. 10 -13 Consequently, plasma angiotensin (Ang) II is increased in association with the rise of angiotensinogen and plasma renin activity during gestation. 14,15 Normal pregnant women are resistant to the pressor effects...

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Section: Discussionmentioning

confidence: 99%

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

et al. 2008

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“…It is likely that ANG II mainly binds to AT 1 receptor and elicits downstream vasocontrictor effects in the placenta. Li X et al [23] examined AT 1 and AT 2 receptor expression in PE and normal placental trophoblast cells and found that both receptors are present in the placenta and that AT 1 receptor predominates [23]. However, Li and colleagues observed that in placentas from PE and intrauterine growth restriction pregnancies the AT 1 receptor expression is decreased compared to normal placental expression.…”

Section: Discussionmentioning

confidence: 99%

“…Receptors for ANG II [2,6,[22][23][24][25], TX [26,27], and ET [28] are present in placental trophoblasts and vasculature. However, the differential effects of each vasoconstrictor in the regulation of placental vasomotor tone have not been simultaneously studied.…”

Section: Introductionmentioning

confidence: 99%

Vasoreactivity of Chorionic Plate Arteries in Response to Vasoconstrictors Produced by Preeclamptic Placentas

2007

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Inadequate blood flow and increased vasoconstriction of the placenta contribute to pregnancy associated disorders such as preeclampsia (PE). Because placental vessels lack autonomic innervation, humoral effects of the placenta must play critical roles in regulation of fetal-placental vascular contractility. In this study, we examined the nature of humoral factors produced by PE trophoblasts on placental vessel contractility using an organ bath perfusion model. Vasomotor responses were studied in vitro using placental chorionic plate arteries. Vessel rings from third branch chorionic plate arteries were dissected from human placentas following normal or PE delivery. The arterial rings were equilibrated in Krebs Henseleit buffer and exposed to placental conditioned medium, which was prepared by culture of villous tissue from PE placentas. Receptor antagonists for angiotensin II (ANG II), thromboxane (TX), and endothelin (ET) were used to determine which humoral factor produced by placental tissue (trophoblasts) was more effective in promoting vasoconstriction. The role of angiotensin converting enzyme (ACE) and non-ACE ANG II generating enzymes in regulation of placental vasomotor tone were also investigated. A total of 80 arterial rings from 48 placentas were studied. Our results showed: 1) enhanced vasomotor tone in arteries from PE placentas compared to those from normal placentas; 2) PE-CM induced vaso-constrictive activity could be partially attenuated by receptor antagonists for TX, ANG II and ET, respectively; and 3) chymostatin (a chymase inhibitor) produced a stronger inhibitory effect than captopril (ACE inhibitor) on PE conditioned medium induced vasoconstriction. Our data demonstrate increased vasocontractility in PE placentas and suggest that the non-ACE pathway is probably a major source of ANG II produced in the human placenta.

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“…It has been reported that both AT1 and AT2 receptors are present in placental tissues [19,20]. To further examine AT1 and AT2 receptor expression on placental vessel cells, VSMCs were exposed to placental conditioned medium for 30 min, 2 h and 4 h. Total cellular protein was extracted and protein expressions were then determined by Western blot analysis.…”

Section: At2 But Not At1 Receptor Expression Is Inducible In Placenmentioning

confidence: 99%

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

Benoit

Zhang

et al. 2008

Placenta

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Our previously published work has shown that non-ACE angiotensin II (Ang II) generating system is dominate in the placenta and may play a critical role in regulation of placental vascular contractile function. In the present study, using a collagen gel contraction assay we further studied contractility of placental vascular smooth muscle cells (VSMCs) in response to factors produced by preeclamptic (PE) placentas. Placental VSMCs/type-1 collagen gels were incubated with PE placental conditioned medium in the presence or absence of inhibitors or receptor blockers. Captopril (an ACE inhibitor), chymostatin (a non-ACE chymase inhibitor), losartan (an AT1 receptor blocker) and PD123,319 (an AT2 receptor blocker) were used to study the specific ACE vs. non-ACE and AT1 vs. AT2 effects on placental VSMC contractility, respectively. Our results showed that chymostatin, but not captopril, and PD123,319, but not losartan, significantly attenuated placental VSMC/collagen gel contraction, p < 0.01, respectively. The inhibitory effects of chymostatin and PD123,319 were dosedependent. Our results suggest that chymase, a non-ACE Ang II generating enzyme, may contribute significantly to Ang II generated in the placenta vascular tissue and that the AT2 receptor may play an important role in the regulation of Ang II induced contractility of placental VSMCs. These results provide new insights into Ang II generation and Ang II receptor regulation of vessel contractile function in the placental vasculature. These results also suggest the potential role of increased chymase activity and altered AT2 receptor function in placental related pregnancy disorders such as preeclampsia and IUGR.

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Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.

Cited by 108 publications

References 47 publications

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

Activation of Local Chorionic Villi Angiotensin II Levels But Not Angiotensin (1-7) in Preeclampsia

Vasoreactivity of Chorionic Plate Arteries in Response to Vasoconstrictors Produced by Preeclamptic Placentas

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

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