BackgroundAortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E2 (PGE2) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurism (AAA) formation. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA.Methods and FindingsImmunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE2 stimulation increased EP4 protein expression (1.4±0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4±0.03- and 1.7±0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE−/− mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01–0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45–87% reduction, P<0.05). Similarly, EP4+/−/ApoE−/− mice exhibited significantly less AAA formation than EP4+/+/ApoE−/− mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl2 application was also reduced in EP4+/− mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10–100 nM decreased MMP-2 activation and IL-6 production (0.6±0.06- and 0.7±0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release.ConclusionAn EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.

E lastic fibers are the largest structures in the extracellular matrix. Beginning with the onset of pulsatile blood flow in the developing aorta and pulmonary artery, smooth muscle cells (SMCs) in the vessel wall produce a complex extracellular matrix that ultimately defines the mechanical properties that are critical for proper function of the neonatal and adult vascular system. 1 As such, hemodynamics and mechanical stress are considered to be the main regulators in the formation of the vascular elastic fiber system during development. 2 Clinical Perspective on p 496The ductus arteriosus (DA) and its connecting elastic arteries (ie, the descending aorta and the main pulmonary trunk) are exposed to essentially the same mechanical forces and hemodynamics. However, since 1914, it has been widely recognized in multiple species that the DA exhibits sparse elastic fibers in the middle layer compared with adjacent elastic arteries, as well as disassembly and fragmentation of the internal elastic lamina. [3][4][5][6][7][8] In the human fetal aorta, newly synthesized uncrosslinked elastin appears at 23 weeks of gestational age to be unevenly distributed on the surface of microfibrils, where it forms continuous strips of variable width. 9 However, the DA exhibits fewer elastic fibers than the aorta. 4,6 This decreased elastogenesis is the hallmark of the vascular remodeling of the DA in humans and a variety of other species. [3][4][5][6][7] It has been suggested that this muscular phenotype of the DA allows it to collapse easily at birth when prostaglandin E 2 (PGE 2 ) is withdrawn and blood flow between the aorta and the pulmonary artery is reduced, thereby permitting immediate postnatal closure of the DA. Conversely, it is known that abnormalities of elastic fibers and elastic lamina are primarily responsible for the persistence of the DA in some human cases.10,11 These abnormalities likely prevent intimal cushion formation and make it difficult to collapse the arterial wall. Therefore, it is Background-Elastic fiber formation begins in mid-gestation and increases dramatically during the last trimester in the great arteries, providing elasticity and thus preventing vascular wall structure collapse. However, the ductus arteriosus (DA), a fetal bypass artery between the aorta and pulmonary artery, exhibits lower levels of elastic fiber formation, which promotes vascular collapse and subsequent closure of the DA after birth. The molecular mechanisms for this inhibited elastogenesis in the DA, which is necessary for the establishment of adult circulation, remain largely unknown. Methods and Results-Stimulation of the prostaglandin E 2 (PGE 2 ) receptor EP4 significantly inhibited elastogenesis and decreased lysyl oxidase (LOX) protein, which catalyzes elastin cross-links in DA smooth muscle cells (SMCs), but not in aortic SMCs. Aortic SMCs expressed much less EP4 than DASMCs. Adenovirus-mediated overexpression of LOX restored the EP4-mediated inhibition of elastogenesis in DASMCs. In EP4-knockout mice, electron microscopi...