Exogenous 17-β estradiol administration blunts progression of established angiotensin II-induced abdominal aortic aneurysms in female ovariectomized mice

Biology of Sex Differences

Sean E. Thatcher²  Xuan Zhang²  Shannon Woody²  Yu Wang²  Yasir Alsiraj²  Richard Charnigo¹  Alan Daugherty³  Lisa A. Cassis² 

[1] Department of Statistics, University of Kentucky, Lexington 40536, KY, USA

[2] Department of Pharmacology and Nutritional Sciences, University of Kentucky, Room 521b, Charles T. Wethington Bldg, Lexington 40536-0200, KY, USA

[3] Department of Physiology, University of Kentucky, Lexington 40536, KY, USA

关键词: Transforming growth factor-beta;    Atherosclerosis;    Estrogen;    Abdominal aortic aneurysms;    Angiotensin;   

Others  :  1219049
DOI  :  10.1186/s13293-015-0030-1

 received in 2015-03-27, accepted in 2015-06-15,  发布年份 2015

【 摘 要 】

Background

Abdominal aortic aneurysms (AAAs) occur predominately in males. However, AAAs in females have rapid growth rates and rupture at smaller sizes. Mechanisms contributing to AAA progression in females are undefined. We defined effects of ovariectomy, with and without 17-β estradiol (E2), on progression of established angiotensin II (AngII)-induced AAAs in female mice.

Methods

We used neonatal testosterone exposures at 1 day of age to promote susceptibility to AngII-induced AAAs in adult female Ldlr ^−/− mice. Females were infused with AngII for 28 days to induce AAAs, and then stratified into groups that were sham, ovariectomized (Ovx, vehicle), or Ovx with E2 administration for 2 months of continued AngII infusions. Aortic lumen diameters were quantified by ultrasound and analyzed by linear mixed model, and maximal AAA diameters were analyzed by one-way ANOVA. Atherosclerosis was quantified en face in the aortic arch. AAA tissue sections were analyzed for cellular composition. We quantified effects of E2 on abdominal aortic smooth muscle cell (SMC) growth, α-actin and transforming growth factor-beta (TGF-β) production, and wound healing.

Results

Serum E2 concentrations were increased significantly by E2. Aortic lumen diameters increased over time in sham-operated and Ovx (vehicle) females, but not in Ovx females administered E2. At day 70, E2 administration decreased significantly aortic lumen diameters compared to Ovx vehicle and sham-operated females. Compared to Ovx females (vehicle), maximal AAA diameters were reduced significantly by E2. AAA tissue sections from Ovx females administered E2 exhibited significant increases in α-actin and decreases in neutrophils compared to Ovx females administered vehicle. In abdominal aortic SMCs, E2 resulted in a concentration-dependent increase in α-actin, elevated TGF-β, and more rapid wound healing. E2 administration to Ovx females also significantly reduced atherosclerotic lesions compared to sham-operated females. This effect was accompanied by significant reductions in serum cholesterol concentrations.

Conclusions

E2 administration to Ovx females abolished progressive growth and decreased severity of AngII-induced AAAs. These effects were accompanied by increased SMC α-actin, elevated TGF-β, and reduced neutrophils. Similarly, E2 administration reduced AngII-induced atherosclerosis. These results suggest that loss of E2 in post-menopausal females may contribute to progressive growth of AAAs.

【 授权许可】

   
2015 Thatcher et al.

【 图 表 】

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【 参考文献 】

• [1]Castleden WM, Mercer JC. Abdominal aortic aneurysms in Western Australia: descriptive epidemiology and patterns of rupture. Br J Surg. 1985; 72:109-112.
• [2]van Vlijmen-van Keulen CJ, Pals G, Rauwerda JA. Familial abdominal aortic aneurysm: a systematic review of a genetic background. European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery. 2002; 24:105-116.
• [3]Henriques TA, Huang J, D'Souza SS, Daugherty A, Cassis LA. Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice. Endocrinology. 2004; 145:3866-3872.
• [4]Henriques T, Zhang X, Yiannikouris FB, Daugherty A, Cassis LA. Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice. Arterioscler, Thromb, Vasc Biol. 2008; 28:1251-1256.
• [5]Zhang X, Thatcher SE, Rateri DL, Bruemmer D, Charnigo R, Daugherty A, Cassis LA. Transient exposure of neonatal female mice to testosterone abrogates the sexual dimorphism of abdominal aortic aneurysms. Circ Res. 2012; 110:e73-e85.
• [6]Szilagyi DE, Smith RF, DeRusso FJ, Elliott JP, Sherrin FW. Contribution of abdominal aortic aneurysmectomy to prolongation of life. Ann Surg. 1966; 164:678-699.
• [7]Brown LC, Powell JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. UK Small Aneurysm Trial Participants. Ann Surg. 1999; 230:289-296.
• [8]Semmens JB, Norman PE, Lawrence-Brown MM, Holman CD. Influence of gender on outcome from ruptured abdominal aortic aneurysm. Br J Surg. 2000; 87:191-194.
• [9]Brown PM, Zelt DT, Sobolev B. The risk of rupture in untreated aneurysms: the impact of size, gender, and expansion rate. J Vasc Surg. 2003; 37:280-284.
• [10]Forbes TL, Lawlor DK, DeRose G, Harris KA. Gender differences in relative dilatation of abdominal aortic aneurysms. Ann Vasc Surg. 2006; 20:564-568.
• [11]Solberg S, Singh K, Wilsgaard T, Jacobsen BK. Increased growth rate of abdominal aortic aneurysms in women. The Tromso study. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery. 2005; 29:145-149.
• [12]Mofidi R, Goldie VJ, Kelman J, Dawson AR, Murie JA, Chalmers RT. Influence of sex on expansion rate of abdominal aortic aneurysms. Br J Surg. 2007; 94:310-314.
• [13]Zhang X, Thatcher S, Wu C, Daugherty A, Cassis LA. Castration of male mice prevents the progression of established angiotensin II-induced abdominal aortic aneurysms. J Vasc Surg. 2014; 61:767-776.
• [14]Ingberg E, Theodorsson A, Theodorsson E, Strom JO. Methods for long-term 17beta-estradiol administration to mice. Gen Comp Endocrinol. 2012; 175:188-193.
• [15]Barisione C, Charnigo R, Howatt DA, Moorleghen JJ, Rateri DL, Daugherty A. Rapid dilation of the abdominal aorta during infusion of angiotensin II detected by noninvasive high-frequency ultrasonography. J Vasc Surg. 2006; 44:372-376.
• [16]Daugherty A, Whitman SC. Quantification of atherosclerosis in mice. Methods Mol Biol. 2003; 209:293-309.
• [17]Ueda K, Lu Q, Baur W, Aronovitz MJ, Karas RH. Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation. Arterioscler, Thromb, Vasc Biol. 2013; 33:1837-1843.
• [18]Thatcher SE, Zhang X, Howatt DA, Yiannikouris F, Gurley SB, Ennis T, Curci JA, Daugherty A, Cassis LA. Angiotensin-converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms. Arterioscler, Thromb, Vasc Biol. 2014; 34:2617-2623.
• [19]Bernelot Moens SJ, Schnitzler GR, Nickerson M, Guo H, Ueda K, Lu Q, Aronovitz MJ, Nickerson H, Baur WE, Hansen U et al.. Rapid estrogen receptor signaling is essential for the protective effects of estrogen against vascular injury. Circulation. 2012; 126:1993-2004.
• [20]Montesano R, Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A. 1988; 85:4894-4897.
• [21]Martin-McNulty B, Tham DM, da Cunha V, Ho JJ, Wilson DW, Rutledge JC, Deng GG, Vergona R, Sullivan ME, Wang YX. 17 Beta-estradiol attenuates development of angiotensin II-induced aortic abdominal aneurysm in apolipoprotein E-deficient mice. Arterioscler, Thromb, Vasc Biol. 2003; 23:1627-1632.
• [22]Ailawadi G, Eliason JL, Roelofs KJ, Sinha I, Hannawa KK, Kaldjian EP, Lu G, Henke PK, Stanley JC, Weiss SJ et al.. Gender differences in experimental aortic aneurysm formation. Arterioscler, Thromb, Vasc Biol. 2004; 24:2116-2122.
• [23]Iafrati MD, Karas RH, Aronovitz M, Kim S, Sullivan TR, Lubahn DB, O'Donnell TF, Korach KS, Mendelsohn ME. Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nat Med. 1997; 3:545-548.
• [24]Watanabe T, Akishita M, Nakaoka T, Kozaki K, Miyahara Y, He H, Ohike Y, Ogita T, Inoue S, Muramatsu M et al.. Estrogen receptor beta mediates the inhibitory effect of estradiol on vascular smooth muscle cell proliferation. Cardiovasc Res. 2003; 59:734-744.
• [25]Haas E, Meyer MR, Schurr U, Bhattacharya I, Minotti R, Nguyen HH, Heigl A, Lachat M, Genoni M, Barton M. Differential effects of 17beta-estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension. 2007; 49:1358-1363.
• [26]Hsu CY, Frankel FR. Effect of estrogen on the expression of mRNAs of different actin isoforms in immature rat uterus. Cloning of alpha-smooth muscle actin message. J Biol Chem. 1987; 262:9594-9600.
• [27]Zhang J, Hess MW, Thurnher M, Hobisch A, Radmayr C, Cronauer MV, Hittmair A, Culig Z, Bartsch G, Klocker H. Human prostatic smooth muscle cells in culture: estradiol enhances expression of smooth muscle cell-specific markers. Prostate. 1997; 30:117-129.
• [28]Li F, Yu X, Szynkarski CK, Meng C, Zhou B, Barhoumi R, White RE, Heaps CL, Stallone JN, Han G. Activation of GPER induces differentiation and inhibition of coronary artery smooth muscle cell proliferation. PLoS One. 2013; 8:e64771.
• [29]Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C et al.. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006; 312:117-121.
• [30]Losy F, Dai J, Pages C, Ginat M, Muscatelli-Groux B, Guinault AM, Rousselle E, Smedile G, Loisance D, Becquemin JP, Allaire E. Paracrine secretion of transforming growth factor-beta1 in aneurysm healing and stabilization with endovascular smooth muscle cell therapy. J Vasc Surg. 2003; 37:1301-1309.
• [31]Wang Y, Ait-Oufella H, Herbin O, Bonnin P, Ramkhelawon B, Taleb S, Huang J, Offenstadt G, Combadiere C, Renia L et al.. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest. 2010; 120:422-432.
• [32]Hong JH, Song C, Shin Y, Kim H, Cho SP, Kim WJ, Ahn H. Estrogen induction of smooth muscle differentiation of human prostatic stromal cells is mediated by transforming growth factor-beta. J Urol. 2004; 171:1965-1969.
• [33]Frazier-Jessen MR, Mott FJ, Witte PL, Kovacs EJ. Estrogen suppression of connective tissue deposition in a murine model of peritoneal adhesion formation. J Immunol. 1996; 156:3036-3042.
• [34]Ashcroft GS, Dodsworth J, van Boxtel E, Tarnuzzer RW, Horan MA, Schultz GS, Ferguson MW. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med. 1997; 3:1209-1215.
• [35]Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. Arterioscler, Thromb, Vasc Biol. 2012; 32:810-814.