17β-Estradiol Attenuates Development of Angiotensin II–Induced Aortic Abdominal Aneurysm in Apolipoprotein E–Deficient Mice

Abstract

Objectives-Angiotensin II (Ang II) promotes vascular inflammation, accelerates atherosclerosis, and induces abdominal aortic aneurysm (AAA). These changes were associated with activation of nuclear factor (NF)-B-mediated induction of proinflammatory genes. The incidence of AAA in this model was higher in male than in female mice, and the vascular effects of estrogen may be associated with anti-inflammatory actions. The present study was undertaken to test the hypothesis that estrogen can attenuate Ang II-induced AAA in apolipoprotein E-deficient mice via its antiinflammatory mechanism. Methods and Results-Infusion of Ang II (1.44 mg/kg per d for 1 month) induced AAA in 90% of the animals (nϭ20) with an expansion of the suprarenal aorta (diameter 1.9Ϯ0.14 mm versus Ͻ1 mm in normal mice). In mice treated with 17␤-estradiol (E2, 0.25-mg subcutaneous pellets), Ang II induced AAA only in 42% of the animals (nϭ19) with a significant reduction of average diameters of the suprarenal aorta (1.5Ϯ0.14 mm). E2 also decreased the expressions of intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and macrophage-colony stimulating factor in the aorta. Key Words: estrogen Ⅲ aneurysm Ⅲ vascular inflammation Ⅲ PPAR Ⅲ gene expression A therosclerosis is an inflammatory disease. 1 Infiltration of monocytes and macrophages into the vessel wall is a major source of proteolytic enzymes, including metalloproteinases, which degrade extracellular matrix, thus impairing the integrity of the artery wall and causing aneurysm. 2 Angiotensin II (Ang II) has been implicated in vascular inflammation and progression of atherosclerosis. 3,4 Chronic infusion of Ang II in apolipoprotein E-deficient (apoE-KO) mice induces aneurysm. 5 We demonstrated that vascular inflammation and aneurysm induced by Ang II were associated with activation of nuclear transcription factor (NF)-Bmediated proinflammatory gene induction. 6,7 It has been reported clinically that the incidence of abdominal aortic aneurysm (AAA) was higher in males than in females. 8 Ang II-induced AAA was also higher in male than in female mice in this model. 9 Estrogen has long been recognized to have vascular actions. 10 Treatment with estrogen reduces atherosclerotic lesion formation in several animal models, including apoE-KO mice, 11,12 even in the absence of lipid-lowering effects. 13 Accumulating evidence suggests that the antiatherosclerotic effects of estrogen can be attributed, at least in part, to anti-inflammatory actions. 14,15 Furthermore, there is in vivo evidence that estrogen inhibits the NF-B pathway, which contributes to anti-inflammatory actions. 16 The present study, therefore, was aimed to test the hypothesis that treatment of 17␤-estradiol can attenuate Ang IIinduced AAA in apoE-KO mice via the mechanism of inhibiting NF-B-mediated proinflammatory gene induction. Conclusions-These MethodsMale apoE-KO mice (Jackson Laboratory, Bar Harbor, Maine) were fed normal rodent chow. When the mice were 5 months ol...

Sex Differences in Abdominal Aortic Aneurysm: The Role of Sex Hormones

“…82 Studies on AAA animal models showed that female sex hormones regulate certain cytokines, chemokines, and other proteins with the majority consisting of members of MAPKs, such as AKT, JNK, ERK, and as a result, they inhibit the expression and activity of certain MMPs, especially MMP2 and MMP9, providing a protective role in aneurysm formation. Moreover, the anti-inflammatory effects of estradiol are mediated through downregulation of several nuclear factor kB (NFkB)edependent proinflammatory mediators such as intracellular adhesion molecule 1, vascular cellular adhesion molecule 1, selectin E, monocyte chemotactic protein 1 (Mcp-1), and macrophage colony-stimulating factor in the aorta, 71 while there is evidence of reciprocal antagonism between estrogen receptors and NF-kB activity. 83 As a result, macrophage and leukocyte infiltration is decreased in the aortic wall and the subsequent production of MMPs, preventing the degradation of ECM in the aortic wall.…”

“…64 The protective effects of estrogens were confirmed by other studies. 69,70 Additionally, Martin-McNultry et al 71 demonstrated that infusion of AngII induced AAA in 90% of Apoe À/À mice, whereas with 17b-estradiol treatment, only 42% of mice developed AAAs. In another AAA study, tamoxifen, a selective estrogen receptor modulator, decreased neutrophil infiltration and increased catalase expression.…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…Both monocyte adhesion and VCAM1 expression were aggravated by oophorectomy and these were reversed after treatment of female animals with E 2 . Later studies performed on hypercholesterolemic Apoe-deficient animals confirmed the pivotal role of endothelial VCAM1 expression for the atheroprotective effects of estrogens (Gourdy et al 2003, Martin-McNulty et al 2003.…”

“…Available results indicate, however, that estrogens reduce atherosclerotic burden in orchidectomized Apoe KO mice on cholesterol-rich diet or infused with angiotensin II (Ang-II) as well as in diabetic Apoe KO mice (Elhage et al 1997a, Tse et al 1999, Martin-McNulty et al 2003. It ought to be emphasized that plasma E 2 concentrations in treated male animals were comparable to those encountered in normal female animals.…”

“…While evidence for the direct regulation of macrophage proliferation by estrogens is lacking, these hormones were shown to modulate bone marrow M-CSF production and reduced aortic expression of M-CSF was found in Apoe-deficient mice treated with E 2 (Sarma et al 1998, Lea et al 1999, Martin-McNulty et al 2003. E 2 was also demonstrated to promote apoptosis of monocytes, monocyte-derived macrophages, and macrophage-derived osteoclasts, and these effects were largely attributed to the upregulation of Fas and Fas ligand (FasL (FASLG)) as well as the activity of caspases 8 and 3 (Carruba et al 2003, Mor et al 2003, Thongngarm et al 2003, Saintier et al 2006, Nakamura et al 2007, Montagna et al 2009).…”