Endothelial cell prostaglandin E2 receptor EP4 is essential for blood pressure homeostasis

Xu, Hu; Fang, Bingying; Du, Shanshan; Wang, Sailun; Li, Qingwei; Jia, Xiaoyun; Bao, Chengzhen; Ye, Lan; Sui, Xue; Qian, Lei; Luan, Zhilin; Yang, Guangrui; Zhao, Feng; Wang, Nanping; Zhang, Xiaoyan; Guan, Youfei

doi:10.1172/jci.insight.138505

Cited by 24 publications

(17 citation statements)

References 48 publications

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“…The main effector of the early hypertensive effect is likely TXA2, as no increase in MABP was observed in TP-deficient mice; on the contrary, MABP decreased for a few min after Abelcet administration. This short-lived hypotensive effect seems to be caused by vasodilatory cyclooxygenase products, such as prostaglandin E2 [ 18 ], PGD2 [ 19 ], and/or prostacyclin (PGI2) [ 20 ]. The prominent role of TXA2 is supported by our previous findings that both amphotericin B containing liposomes and direct C activators increased plasma TXB2 concentration in both mice and rats [ 2 , 12 , 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane

et al. 2022

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Liposomal amphotericin B (Abelcet) can cause infusion (anaphylactoid) reactions in patients whose mechanism is poorly understood. Here, we used mice to investigate the role of complement (C) receptors and the cellular sources of vasoactive mediators in these reactions. Anesthetized male NMRI and thromboxane prostanoid receptor (TP) or cyclooxygenase-1 (COX-1)-deficient and wild type C57Bl6/N mice were intravenously injected with Abelcet at 30 mg/kg. Mean arterial blood pressure (MABP) and heart rate (HR) were measured. In untreated mice, Abelcet caused a short (15 min) but large (30%) increase in MABP. C depletion with cobra venom factor (CVF) and inhibition of C5a receptors with DF2593A considerably prolonged, while C3aR inhibition with SB290157 significantly decreased the hypertensive effect. Likewise, the hypertensive response was abolished in COX-1- and TP-deficient mice. CVF caused a late hypertension in TP-deficient mice. Both macrophage depletion with liposomal clodronate and blockade of platelet GPIIb/IIIa receptors with eptifibatide prolonged the hypertensive effect. The early phase of the hypertensive effect is COX-1- and TP-receptor-dependent, partly mediated by C3aR. In contrast, the late phase is under the control of vasoactive mediators released from platelets and macrophages subsequent to complement activation and C5a binding to its receptor.

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Section: Discussionmentioning

confidence: 99%

The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane

et al. 2022

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“…In vascular endothelial cells (ECs), EP4 receptor mediated PGE2-elicited acute vasodilator response is dependent on endothelium derived NO production by coupling with endothelial nitric oxide synthase (eNOS) ( 73 , 74 ). The EP4 agonist PGE1-OH and CAY10580 markedly reduced BP levels in Dahl salt-sensitive hypertensive rats ( 75 ). In renal vascular system, EP4 receptor play a paradoxical role in activating renin-angiotensin-aldosterone system.…”

Section: Ep4 Receptormentioning

confidence: 99%

Roles of EP Receptors in the Regulation of Fluid Balance and Blood Pressure

Wang

et al. 2022

Front. Endocrinol.

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Prostaglandin E2 (PGE2) is an important prostanoid expressing throughout the kidney and cardiovascular system. Despite the diverse effects on fluid metabolism and blood pressure, PGE2 is implicated in sustaining volume and hemodynamics homeostasis. PGE2 works through four distinct E-prostanoid (EP) receptors which are G protein-coupled receptors. To date, pharmacological specific antagonists and agonists of all four subtypes of EP receptors and genetic targeting knockout mice for each subtype have helped in uncoupling the diverse functions of PGE2 and discriminating the respective characteristics of each receptor. In this review, we summarized the functions of individual EP receptor subtypes in the renal and blood vessels and the molecular mechanism of PGE2-induced fluid metabolism and blood pressure homeostasis.

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“…The diverse effects of PGE 2 on vascular functions may be due to the characteristic of tissue distribution of the receptors. Recently, Xu et al reported that EC-specific KO and overexpression of EP4 resulted in higher and lower BP compared with control mice, respectively [ 56 ], under both basal and high-salt diet conditions. Physiological roles of PGs on BP regulation may be still controversial; however, the recent report clearly indicates a hypotensive potential of PGE 2 -EP4 signaling via enhancing NO production in ECs.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…The possible mechanisms have been well reviewed [ 57 , 58 , 59 ]; herein, we shortly highlight recent findings on this topic ( Table 3 ). Among various subpopulations of immune cells, previous reports indicate that T cells especially have diverse contributions to the etiology [ 56 ]. In particular, CD4 + - and regulatory T cell (Treg)-mediated pathological cascades have been raised in several recent studies.…”

Section: Mouse Modelsmentioning

confidence: 99%

Genetic Modifications to Alter Blood Pressure Level

OHARA

Nabika

2022

Biomedicines

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Genetic manipulation is one of the indispensable techniques to examine gene functions both in vitro and in vivo. In particular, cardiovascular phenotypes such as blood pressure cannot be evaluated in vitro system, necessitating the creation of transgenic or gene-targeted knock-out and knock-in experimental animals to understand the pathophysiological roles of specific genes on the disease conditions. Although genome-wide association studies (GWAS) in various human populations have identified multiple genetic variations associated with increased risk for hypertension and/or its complications, the causal links remain unresolved. Genome-editing technologies can be applied to many different types of cells and organisms for creation of knock-out/knock-in models. In the post-GWAS era, it may be more worthwhile to validate pathophysiological implications of the risk variants and/or candidate genes by creating genome-edited organisms.

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Endothelial cell prostaglandin E2 receptor EP4 is essential for blood pressure homeostasis

Cited by 24 publications

References 48 publications

The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane

The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane

Roles of EP Receptors in the Regulation of Fluid Balance and Blood Pressure

Genetic Modifications to Alter Blood Pressure Level

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