EP1c Times for Angiotensin
EP1 Receptors Facilitate Angiotensin II–Induced Vascular Dysfunction
A relatively recent concept is that vascular dysfunction plays a key role in cognitive impairment, as well as stroke. Impaired neurovascular coupling, probably in part through activation of the angiotensin II type 1 receptor, is central to cerebrovascular dysfunction.1 Reactive oxygen species clearly are important mediators of the deleterious vascular effects of angiotensin II. The evidence seemed to favor the concept that angiotensin II, perhaps through activation of NADPH oxidase, releases superoxide, which scavenges NO to produce cerebral vascular dysfunction.1
However, just when we thought that we understood mechanisms by which angiotensin II produces cerebrovascular dysfunction, Capone et al2 in this issue of Hypertension present compelling evidence that products of cyclooxygenase (COX) metabolism are important facilitating factors for angiotensin II signaling in cerebral blood vessels. The authors report that prostaglandin E2 (PGE2) and the type 1 PGE2 (EP1) receptor are required for endothelial dysfunction and impaired neurovascular coupling induced by acute administration of angiotensin II.2 Because the hypothesis is novel and important for our understanding of angiotensin II effects, it is desirable to have multiple lines of evidence to support the conclusion. This indeed the authors have accomplished, because they use several genetically altered mice and pharmacological inhibitors to build their case.
EP1 Receptors and COX-1 in Angiotensin II–Induced Vascular Dysfunction
COX-1 is involved in synthesis and release of an endothelium-derived contracting factor.3 Pressor responses to angiotensin II are attenuated in COX-1 knockout mice and in mice treated with a COX-1 inhibitor, whereas opposite effects (augmentation of responses to angiotensin II) are found with COX-2 inhibitors.4 Interestingly, angiotensin II increases COX-1 and decreases COX-2 expression in murine mesenteric arteries through a reactive oxygen species–independent mechanism.5 These findings suggest that a product of arachidonic acid metabolism, through COX-1, interacts with angiotensin II to induce hypertension.
Similarly, several studies have implicated a prostanoid receptor in vascular dysfunction produced by angiotensin II. SQ29548, a thromboxane A and EP1 receptor antagonist, attenuates vascular dysfunction induced by angiotensin II.5 Moreover, in mice deficient in thromboxane or EP1 receptors, mortality and the pressor response to infusion of angiotensin II are attenuated.6,7
Capone et al2 demonstrates that COX-1–dependent formation of PGE2 and the EP1 receptor are necessary for angiotensin II–induced impairment in neurovascular coupling and cerebrovascular dysfunction. The authors demonstrated that COX-1 and the EP1 receptor are expressed in microglia and blood vessels, respectively. Cerebrovascular dysfunction and impaired neurovascular coupling after an acute infusion of angiotensin II are attenuated in mice treated with a COX-1 inhibitor, but not a COX-2 inhibitor, and in mice deficient in COX-1. Angiotensin II did not increase PGE2 synthesis in the brain, but PGE2 superfusion restored susceptibility of cerebral vessels to angiotensin II–induced dysfunction after COX-1 inhibition.
In addition, effects of angiotensin II are reduced in mice treated with an EP-1 receptor antagonist and in EP-1 knockout mice. EP1 receptors are also required for angiotensin II–induced increase of reactive oxygen species. Therefore, PGE2 (a COX-1 product) and EP1 receptors are required for deleterious effects of angiotensin II in the cerebral circulation.
EP1 Receptors Are Important for the Vascular Effects of Angiotensin II, But What Is the Mechanism?
Several concurrent mechanisms may explain the cross-talk between EP1 and angiotensin II receptors (Figure). First, Capone et al2 propose that EP1 receptor activation may increase intracellular calcium concentrations and facilitate activation of the NADPH oxidase. Different results have been published before, where PGE2 attenuated the increase in intracellular calcium induced by angiotensin II in smooth muscle cells from rat preglomerular arterioles.8 Second, activation of EP1 receptors may modulate the activity of regulatory kinases or regulators of G protein signaling (RGS proteins) to facilitate intracellular signaling in response to angiotensin II. Thus, angiotensin II may work synergistically with prostaglandins to induce vascular dysfunction. Third, we speculate that EP1 receptors may physically regulate the activity of angiotensin II type 1 receptors through heterodimerization. Both angiotensin II and PGE2 receptors are G protein–coupled receptors, and it is now known that heterodimerization of G protein–coupled receptors alters the trafficking and activity of receptors at the plasma membrane.9 For example, angiotensin II type 1 and EP1 receptors heterodimerize and modulate the activity of β-adrenergic receptors.9 It is not known, however, whether angiotensin II receptors dimerize with EP1 receptors. Finally, it is possible that facilitation of angiotensin II signaling by PGE2 exists only in the context of increased blood pressure.10 It would be of interest to know whether EP1 receptor facilitation of angiotensin II–induced vascular dysfunction is present in the absence of hypertension, for example, during nonpressor doses of angiotensin II in vivo.
Is Prostaglandin Signaling Detrimental for Cerebral Vascular Function?
Although the observation that PGE2 contributes to angiotensin II-induced cerebral vascular dysfunction is convincing,2 several other lines of evidence point toward a beneficial role of PGE2 and EP1 receptors in vascular function. Mice deficient in microsomal PGE2 synthase have a profound pressor response and increased oxidative stress in aorta after treatment with nonpressor doses of angiotensin II.10 Moreover, PGE2 evoked dilation of the mouse basilar artery ex vivo.11 EP1 receptors also facilitate NO release during neurogenic vasodilation in porcine basilar arteries.12 Finally, in a rat model of hypertension associated with increased formation of angiotensin II, COX-1 inhibition did not attenuate vascular dysfunction or hypertension.13 The conflicting results may be explained by differences in model (in vivo versus ex vivo preparations), vascular bed (cerebral cortical vessels versus basilar arteries or systemic vessels), and duration of treatment (acute versus chronic). Therefore, studies are needed to clarify the protective or deleterious effects of different isoforms of PGE2 synthase and EP1 receptors in the function of cerebral and other vessels during chronic infusions of angiotensin II.
Capone et al2 provide evidence for a crucial role of prostanoid metabolism and signaling in the regulation of cerebrovascular function. Inhibition of COX-1 or EP1 receptors attenuated the deleterious vascular effects of angiotensin II. Development of specific prostaglandin E synthase inhibitors might be a therapeutic target for cerebrovascular disease. It will be of interest to clarify mechanisms responsible for cross-talk between prostaglandin and angiotensin II pathways, especially in chronic hypertension.
We thank Drs Mark Chappell, Frank Faraci, and Rory Fisher for their valuable suggestions.
Sources of Funding
This work was supported by a Fulbright Scholarship and American Heart Association Predoctoral Fellowship 0815525G (to R.A.P.-S.), a Carver Program of Excellence, and National Institutes of Health grants NS-24621 and HL-62984 (to D.D.H.).
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Fang X, Faraci FM, Kaduce TL, Harmon S, Modrick ML, Hu S, Moore SA, Falck JR, Weintraub NL, Spector AA. 20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase. Am J Physiol Heart Circ Physiol. 2006; 291: H2301–H2307.
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