The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth

Nguyen, Minh H.; Camenisch, Todd D.; Snouwaert, John N.; Hicks, Elizabeth; Coffman, Thomas M.; Anderson, Page A.W.; Malouf, Nadia N.; Koller, Beverly H.

doi:10.1038/36342

Cited by 335 publications

(248 citation statements)

References 22 publications

Supporting

Mentioning

228

Contrasting

Unclassified

Order By: Relevance

“…Moreover, we and others have previously shown that ductus arteriosus closure is dependent on activation of the EP4 receptor for PGE 2 (43,44), yet mPGES1-deficient mice undergo normal closure of the ductus arteriosus (21,32). Taken together, these data indicate that there are alternative, mPGES1-independent pathways for PGE 2 synthesis in the intact animal.…”

Section: Discussionsupporting

confidence: 60%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Prostaglandin E 2 (PGE 2 ) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE 2 is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE 2 has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE 2 in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1 ؉/؉ and mPges1 ؊/؊ mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high-or low-salt diets. The furosemide-induced increase in urinary PGE 2 excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE 2 , but there are other pathways that lead to renal PGE 2 synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

show abstract

Section: Discussionsupporting

confidence: 60%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…The ductus arteriosus closes following birth as a consequence of a complex process involving smooth muscle cell proliferation, migration and extracellular matrix deposition. Prostaglandins are important mediators for triggering this process, as demonstrated by the patent ductus and postnatal hypoxic death of mice lacking prostaglandin receptor E4 (26) and of mice lacking both cyclooxygenase 1 and 2 (27). Although we have not observed any postnatal death in our 129-apoE mice, we have found that both the aortic and pulmonary artery sides of the ductus arteriosus remain open in many of the adult 129-apoE mice and form funnellike pockets.…”

Section: Discussionmentioning

confidence: 68%

Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

et al. 2007

View full text Add to dashboard Cite

There are well-known genetic background effects on atherosclerosis susceptibility in mice. To study the basis of these effects, we have generated the apolipoprotein E-null mutation in mouse embryonic stem cells of 129/SvEv origin, maintained it in the inbred strain (129-apoE), and compared these mice with those previously made in strain 129/Ola and backcrossed to a C57BL/6 genetic background (B6-apoE). Plasma cholesterol and triglyceride levels in the apoE-129 mice are twice the levels in apoE-B6, and both VLDL/chylomicron remnants and HDL particles are increased. Regression analysis of plaque size relative to the age of mice suggests that the initiation of atherosclerotic plaque development at the aortic root is slower in 129-apoE mice (intercept at 3.9 mo in females and 4.1 mo in males) than in B6-apoE mice (1.3 mo in females and 2.8 mo in males). In contrast, 129-apoE mice develop extensive plaques in the aortic arches earlier than B6-apoE mice. Distinct differences in the geometry of the aortic arch between the two strains suggest that anatomical differences may contribute to the effects of genetic background on atherosclerosis. The 129-apoE/B6-apoE pair thus provides a tool to study factors governing the relation between arterial geometry and the location of plaque development. Keywordsanimal model; atherosclerotic plaque distribution; cholesterol; aortic arch; aortic root; inbred mouse strain; ductus arteriosus Well-characterized animal models are essential for the study of common human diseases such as those involving the cardiovascular system. The first practical mouse model of atherosclerosis was developed by inactivating the gene coding for apolipoprotein E (apoE) (1-3). ApoE plays a central role in lipoprotein metabolism and is required for efficient receptor-mediated plasma clearance by the liver of chylomicron remnants and very low-density lipoprotein (VLDL)-remnant particles (4). Lack of apoE in the mutant mice results in an increased accumulation of cholesterol-enriched remnant particles and four times normal plasma cholesterol levels even Correspondence to: Dr. Nobuyo Maeda, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. Phone: 919-966-6912, Fax: 919-966-8800. E-mail: nobuyo@med.unc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. when the mice are fed regular low-fat, low-cholesterol chow. The apoE-deficient mice spontaneously develop atherosclerotic plaques similar to those seen in humans (5,6), with the exception that the spontaneo...

show abstract

“…EP 1 is a constrictive receptor and EP 3 induces a decline in cAMP, inhibiting smooth muscle relaxation (Narumiya and FitzGerald 2001). The main receptor responsible for PGE 2 -induced DA relaxation varies among mammalian species and was reported as EP 4 in rabbits (Smith 1998;Smith et al 1994;Smith and McGrath 1995), mice (Nguyen et al 1997), rats , lambs (Waleh et al 2004), baboon (Waleh et al 2004), and humans (Leonhardt et al 2003), and as EP 2 in pigs (Bhattacharya et al 1999) and lambs (Bouayad et al 2001). The cAMP-inhibiting EP 3 receptor is also present in the rabbit and piglet DA, modulating the dilating eVect of PGE 2 (Bhattacharya et al 1999;Smith 1998;Smith et al 1994;Smith and McGrath 1995).…”

Section: Introductionmentioning

confidence: 99%

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

et al. 2008

View full text Add to dashboard Cite

Prostaglandin E 2 (PGE 2 ) is the major vasodilator prostanoid of the mammalian ductus arteriosus (DA). In the present study we analyzed the response of isolated DA rings from 15-, 19-and 21-day-old chicken embryos to PGE 2 and other vascular smooth muscle relaxing agents acting through the cyclic AMP signaling pathway. PGE 2 exhibited a relaxant response in the 15-day DA, but not in the 19-and 21-day DA. Moreover, high concentrations of PGE 2 (¸3 M in 15-day and ¸1 M in 19-day and 21-day DA) induced contraction of the chicken DA. The presence of the TP receptor antagonist SQ29,548, unmasked a relaxant eVect of PGE 2 in the 19-and 21-day DA and increased the relaxation induced by PGE 2 in the 15-day DA. The presence of the EP receptor antagonist AH6809 abolished PGE 2 -mediated relaxation. The relaxant responses induced by PGE 2 and the -adrenoceptor agonist isoproterenol, but not those elicited by the adenylate cyclase activator forskolin or the phosphodiesterase 3 inhibitor milrinone, decreased with maturation. High oxygen concentrations (95%) decreased the relaxation to PGE 2 . The relaxing potency and eYcacy of isoproterenol and milrinone were higher in the pulmonary than in the aortic side of the DA, whereas no regional diVerences were found in the response to PGE 2 . We conclude that, in contrast to the mammalian situation, PGE 2 is a weak relaxant agent of the chicken DA and, with advancing incubation, it even stimulates TP vasoconstrictive receptors.

show abstract

The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth

Cited by 335 publications

References 22 publications

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

Contact Info

Product

Resources

About