Abstract
Abdominal aortic aneurysms (AAA) result from maladaptive remodeling of the vascular wall and reduces structural integrity. Angiotensin II (AngII) infusion has become a standard laboratory model for studying AAA initiation and progression. We determined the different vasoactive responses of various mouse arteries to Ang II. Ex vivo isometric tension analysis was conducted on 18-week-old male C57BL/6 mice (n = 4) brachiocephalic arteries (BC), iliac arteries (IL), and abdominal (AA) and thoracic aorta (TA). Arterial rings were mounted between organ hooks, gently stretched and an AngII dose response was performed. Rings were placed in 4% paraformaldehyde for immunohistochemistry analysis to quantify peptide expression of angiotensin type 1 (AT1R) and 2 receptors (AT2R) in the endothelium, media, and adventitia. Results from this study demonstrated vasoconstriction responses in IL were significantly higher at all AngII doses when compared to BC, and TA and AA responses (maximum constriction—IL: 68.64 ± 5.47% vs. BC: 1.96 ± 1.00%; TA: 3.13 ± 0.16% and AA: 2.75 ± 1.77%, p < 0.0001). Expression of AT1R was highest in the endothelium of IL (p < 0.05) and in the media and (p < 0.05) adventitia (p < 0.05) of AA. In contrast, AT2R expression was highest in endothelium (p < 0.05), media (p < 0.01, p < 0.05) and adventitia of TA. These results suggest that mouse arteries display different vasoactive responses to AngII, and the exaggerated response in IL arteries may play a role during AAA development.
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Sakalihasan N, Michel JB, Katsargyris A, Kuivaniemi H, Defraigne JO, Nchimi A, Powell JT, Yoshimura K, Hultgren R (2018) Abdominal aortic aneurysms. Nat Rev Dis Primers 4:34
Malekzadeh S, Fraga-Silva RA, Trachet B, Montecucco F, Mach F, Stergiopulos N (2013) Role of the renin-angiotensin system on abdominal aortic aneurysms. Eur J Clin Invest 43:1328–1338
Lu HY, Shih CM, Huang CY, Wu ATH, Cheng TM, Mi FL, Shih CC (2020) Galectin-3 modulates macrophage activation and contributes smooth muscle cells apoptosis in abdominal aortic aneurysm pathogenesis. Int J Mol Sci 21:8257
Wang X, Parasaram V, Dhital S, Nosoudi N, Hasanain S, Lane BA, Lessner SM, Eberth JF, Vyavahare NR (2021) Systemic delivery of targeted nanotherapeutic reverses angiotensin II-induced abdominal aortic aneurysms in mice. Sci Rep 11:8584
Trachet B, Piersigilli A, Fraga-Silva RA, Aslanidou L, Sordet-Dessimoz J, Astolfo A, Stampanoni MF, Segers P, Stergiopulos N (2016) Ascending aortic aneurysm in angiotensin II-infused mice: formation, progression, and the role of focal dissections. Arterioscler Thromb Vasc Biol 36:673–681
Daugherty A, Cassis LA, Lu H (2011) Complex pathologies of angiotensin II-induced abdominal aortic aneurysms. J Zhejiang Univ Sci B 12:624–628
van Geel PP, Pinto YM, Voors AA, Buikema H, Oosterga M, Crijns HJ, van Gilst WH (2000) Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension 35:717–721
Zulli A, Hare DL, Buxton BF, Widdop RE (2014) Vasoactive role for angiotensin II type 2 receptors in human radial artery. Int J Immunopathol Pharmacol 27:79–85
Xie-Zukauskas H, Das J, Short BL, Gutkind JS, Ray PE (2013) Heparin inhibits angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways. Vascul Pharmacol 58:313–318
Zhou Y, Dirksen WP, Babu GJ, Periasamy M (2003) Differential vasoconstrictions induced by angiotensin II: role of AT1 and AT2 receptors in isolated C57BL/6J mouse blood vessels. Am J Physiol Heart Circ Physiol 285:H2797–H2803
Moltzer E, te Riet L, Swagemakers SM, van Heijningen PM, Vermeij M, van Veghel R, Bouhuizen AM, van Esch JH, Lankhorst S, Ramnath NW, de Waard MC, Duncker DJ, van der Spek PJ, Rouwet EV, Danser AH, Essers J (2011) Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1) receptor blockade. PLoS ONE 6:e23411
Zhou Y, Chen Y, Dirksen WP, Morris M, Periasamy M (2003) AT1b receptor predominantly mediates contractions in major mouse blood vessels. Circ Res 93:1089–1094
Daeichin V, Sluimer JC, van der Heiden K, Skachkov I, Kooiman K, Janssen A, Janssen B, Bosch JG, de Jong N, Daemen MJ, van der Steen AF (2015) Live observation of atherosclerotic plaque disruption in apolipoprotein E-deficient mouse. Ultrasound Int Open 1:E67-71
Cha J, Ivanov V, Ivanova S, Kalinovsky T, Rath M, Niedzwiecki A (2010) Evolution of angiotensin II-mediated atherosclerosis in ApoE KO mice. Mol Med Rep 3:565–570
Qaradakhi T, Gadanec LK, Tacey AB, Hare DL, Buxton BF, Apostolopoulos V, Levinger I, Zulli A (2019) The effect of recombinant undercarboxylated osteocalcin on endothelial dysfunction. Calcif Tissue Int 105:546–556
Qaradakhi T, Matsoukas MT, Hayes A, Rybalka E, Caprnda M, Rimarova K, Sepsi M, Büsselberg D, Kruzliak P, Matsoukas J, Apostolopoulos V, Zulli A (2017) Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms. Cardiovasc Ther 35:6
Nehme A, Zouein FA, Zayeri ZD, Zibara K (2019) An update on the tissue renin angiotensin system and its role in physiology and pathology. J Cardiovasc Dev Dis 6:14
Paz Ocaranza M, Riquelme JA, García L, Jalil JE, Chiong M, Santos RAS, Lavandero S (2020) Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 17:116–129
Ferreira AJ, Santos RA, Bradford CN, Mecca AP, Sumners C, Katovich MJ, Raizada MK (2010) Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension 55:207–213
Kaschina E, Scholz H, Steckelings UM, Sommerfeld M, Kemnitz UR, Artuc M, Schmidt S, Unger T (2009) Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. Atherosclerosis 205:396–403
Rateri DL, Davis FM, Balakrishnan A, Howatt DA, Moorleghen JJ, O’Connor WN, Charnigo R, Cassis LA, Daugherty A (2014) Angiotensin II induces region-specific medial disruption during evolution of ascending aortic aneurysms. Am J Pathol 184:2586–2595
Tsunemi K, Takai S, Nishimoto M, Yuda A, Hasegawa S, Sawada Y, Fukumoto H, Sasaki S, Miyazaki M (2002) Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta. Hypertens Res 25:817–822
Bruemmer D, Daugherty A, Lu H, Rateri DL (2011) Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms. Ann N Y Acad Sci 1245:7–10
Trachet B, Aslanidou L, Piersigilli A, Fraga-Silva RA, Sordet-Dessimoz J, Villanueva-Perez P, Stampanoni MFM, Stergiopulos N, Segers P (2017) Angiotensin II infusion into ApoE-/- mice: a model for aortic dissection rather than abdominal aortic aneurysm? Cardiovasc Res 113:1230–1242
Guo DF, Sun YL, Hamet P, Inagami T (2001) The angiotensin II type 1 receptor and receptor-associated proteins. Cell Res 11:165–180
Bian J, Zhang S, Yi M, Yue M, Liu H (2018) The mechanisms behind decreased internalization of angiotensin II type 1 receptor. Vascul Pharmacol 103–105:1–7
Ding J, Yu M, Jiang J, Luo Y, Zhang Q, Wang S, Yang F, Wang A, Wang L, Zhuang M, Wu S, Zhang Q, Xia Y, Lu D (2020) Angiotensin II decreases endothelial nitric oxide synthase phosphorylation via AT1R Nox/ROS/PP2A pathway. Front Physiol 11:566410
DeRoo E, Stranz A, Yang H, Hsieh M, Se C, Zhou T (2022) Endothelial dysfunction in the pathogenesis of abdominal aortic aneurysm. Biomolecules 12:509
Yu B, Shahid M, Egorina EM, Sovershaev MA, Raher MJ, Lei C, Wu MX, Bloch KD, Zapol WM (2010) Endothelial dysfunction enhances vasoconstriction due to scavenging of nitric oxide by a hemoglobin-based oxygen carrier. Anesthesiology 112:586–594
St Paul A, Corbett CB, Okune R, Autieri MV (2020) Angiotensin II, hypercholesterolemia, and vascular smooth muscle cells: a perfect trio for vascular pathology. Int J Mol Sci 21:4525
Yaghini FA, Song CY, Lavrentyev EN, Ghafoor HU, Fang XR, Estes AM, Campbell WB, Malik KU (2010) Angiotensin II-induced vascular smooth muscle cell migration and growth are mediated by cytochrome P450 1B1-dependent superoxide generation. Hypertension 55:1461–1467
Varga A, Gruber N, Forster T, Piros G, Havasi K, Jebelovszki E, Csanády M (2004) Atherosclerosis of the descending aorta predicts cardiovascular events: a transesophageal echocardiography study. Cardiovasc Ultrasound 2:21
Franchin M, Grassi V, Piffaretti G, Bush RL, Tozzi M, Lomazzi C (2021) Thoracic endovascular aortic repair in “shaggy thoracic aortic aneurysms.” Cardiovasc Intervent Radiol 44:220–229
Vuorio A, Kovanen PT, Raal F (2022) Statin needs to be continued during paxlovid therapy in COVID-19. Clin Infect Dis 75:2281–2282
Duke LM, Widdop RE, Kett MM, Evans RG (2005) AT(2) receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension. Br J Pharmacol 144:486–492
You D, Loufrani L, Baron C, Levy BI, Widdop RE, Henrion D (2005) High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation 111:1006–1011
Moltzer E, Verkuil AV, van Veghel R, Danser AH, van Esch JH (2010) Effects of angiotensin metabolites in the coronary vascular bed of the spontaneously hypertensive rat: loss of angiotensin II type 2 receptor-mediated vasodilation. Hypertension 55:516–522
Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, Inagami T (2001) Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation 104:346–351
Senbonmatsu T, Ichihara S, Price E Jr, Gaffney FA, Inagami T (2000) Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest 106:R25-29
Sun Y, Li Y, Wang M, Yue M, Bai L, Bian J, Hao W, Sun J, Zhang S, Liu H (2020) Increased AT2R expression is induced by AT1R autoantibody via two axes, -Klf-5/IRF-1 and circErbB4/miR-29a-5p, to promote VSMC migration. Cell Death Dis 11:432
Sangha GS, Busch A, Acuna A, Berman AG, Phillips EH, Trenner M, Eckstein HH, Maegdefessel L, Goergen CJ (2019) Effects of iliac stenosis on abdominal aortic aneurysm formation in mice and humans. J Vasc Res 56:217–229
Vollmar JF, Paes E, Pauschinger P, Henze E, Friesch A (1989) Aortic aneurysms as late sequelae of above-knee amputation. Lancet 2:834–835
Crawford JD, Chivukula VK, Haller S, Vatankhah N, Bohannan CJ, Moneta GL, Rugonyi S, Azarbal AF (2016) Aortic outflow occlusion predicts rupture of abdominal aortic aneurysm. J Vasc Surg 64:1623–1628
Hoshina K, Sho E, Sho M, Nakahashi TK, Dalman RL (2003) Wall shear stress and strain modulate experimental aneurysm cellularity. J Vasc Surg 37:1067–1074
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The authors would like to thank the Institute for Health and Sport, Victoria University for their support. L.K.G. and K.R.M. are recipients of Victoria University postgraduate scholarships.
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LKG, KRM, wrote the main manuscript text LKG, KRM, PK, MC, LG collected and analysed data RP, JD prepared figures PK, VA, AZ designed the study All authors reviewed the manuscript.
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The authors declare no conflict of interest. Associate Professor Anthony Zulli co-owns Zultek Engineering, the provider of product OB8 used for isometric tension analysis.
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Gadanec, L.K., McSweeney, K.R., Kubatka, P. et al. Angiotensin II constricts mouse iliac arteries: possible mechanism for aortic aneurysms. Mol Cell Biochem 479, 233–242 (2024). https://doi.org/10.1007/s11010-023-04724-0
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DOI: https://doi.org/10.1007/s11010-023-04724-0