Bilateral Common Carotid Artery Ligation in Sheep. Could These Animals be Used as Human Models for Vascular and Cerebral Research?

Open access


Experimental animals are still used in today’s medicine to understand better physiological or pathological processes, or to develop, for example better vascular prostheses. For that reason, these animals must show some similarities with humans, from the anatomical to the physiological point of view. When developing vascular prostheses, we have to evaluate if the graft will react in the expected way and if during experimental research there will be some factors that might influence the proper functioning of vascular prostheses in the human body. We observed the consequences of bilateral common carotid artery ligation (BCCAL) or Sham operation in seventeen healthy Merinolandschaf / Württemberg sheep, aged between 2 and 4 years, after testing new types of carbon-coated ARTECOR® and ADIPOGRAFT Ra 1vk 7/350 vascular prostheses. After the follow-up period the prostheses were extirpated, so the blood supply was provided from the vertebral arteries. Sheep in both groups were not sacrificed, but were observed for 18 months. After the observation period all sheep showed no physical or neurological changes and all are still alive. Animal responses to BCCAL are different, depending on the animal species, age, and condition. In sheep, bilateral blocking of the blood fl ow in the carotid bed seems to be conceivable since the brain was sufficiently supplied with blood from the vertebral arteries.

1. Byrom MJ, Bannon PG, White GH, Ng MKC: Animal models for the assessment of novel vascular conduits. J Vasc Surg 2010, 52(1):176-195.

2. Toledo-Pereyra LH: The ethics of surgical research. J Invest Surg 2003, 16(3):119-121.

3. Aboud E, Suarez CE, Al-Mefty O, Yasargil MG: New alternative to animal models for surgical training. Altern Lab Anim 2004, 32(suppl 1):501-07.

4. Peirovi H, Farnia P, Bahrami A, Mohsenifar Z, Kashani BA, Ghanavi JE: Modifi ed sleeve anastomosis in large muscular arteries of sheep. Eur J Vasc Endovasc Surg 2005, 30(4):381-385.

5. Conn PM (ed): Animal models for atherosclerosis, restenosis, and endovascular aneurysm repair. In: Sourcebook of models for biomedical research. Totowa, New Jersey, USA: Humana Press; 2008, 3-27, 355-397.

6. Swartz DD, Andreadis ST: Animal models for vascular tissue-engineering. Curr Opin Biotechnol 2013, 24(5):916-925.

7. Zaragoza C, Gomez-Guerrero C, Martin-Ventura JL, Blanco-Colio L, Lavin B, Mallavia B, Tarin C, Mas S, Ortiz A, Egido J: Animal models of cardiovascular diseases. J Biomed Biotechnol 2011, 497841.

8. Narayanaswamy M, Wright KC, Kandarpa K: Animal models for atherosclerosis, restenosis and endovascular graft research. J Vasc Interv Radiol 2000, 11(1):5-17.

9. Syedain ZH, Meier LA, Lahti MT, Johnson SL, Tranquillo RT: Implantation of completely biological engineered grafts following decellularization into the sheep femoral artery. Tissue Eng Part A 2014, 20(11-12):1726-1734.

10. Ao PY, Hawthorne WJ, Vicaretti M, Fletcher JP: Development of intimal hyperplasia in six different vascular prostheses. Eur J Vasc Endovasc Surg 2000, 20(3):241-249.

11. Trantina-Yates A, Weissenstein C, Human P, Zilla P: Stentless bioprosthetic heart valve research: sheep versus primate model. Ann Thorac Surg 2001, 71(5 suppl):S422-427.

12. Podlaha J, Dvořák M, Věra Žižková, Dvořák R, Kabeš R, Jelínek M, Veselý K: Experimental assessment of a new type of carbon-coated ARTECOR® vascular prosthesis in sheep. Acta Vet Brno 2009, 78 (1):115-120.

13. Goodman SL: Sheep, pig, and human platelet-material interactions with model cardiovascular biomaterials. J Biomed Mater Res 1999, 45(3):240-250.

14. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS: Comparison of t reatment effects between animal experiments and clinical trials: systematic review. BMJ 2007, 334(7586):197. Epub.

15. Ashwini CA, Shu bha R, Jayanthi K: Comparative ana tomy of the circle of Willis in man, cow, sheep, goat and pig. Neuroanatomy 2008, 7:54-65.

16. Lee RM: Morphology of c erebral arteries. Pharmacol Ther 1995, 66(1):149-173.

17. McDonald DA, Po tter JM: The distribution of blood to the brain. J Physiol 1951, 114(3):356-371.

18. Haouzi P, Chenuel B, Chalon B, Braun M, Bedez Y, Tousseul B, Claudon M, Gille JP: Isolation of th e arterial supply to the carotid and central chemoreceptors in the sheep. Exp Physiol 2003, 88(5):581-594.

19. Tilman P, Carson SN, Talken L: Platelet function and coagulation parameters in sheep during experimental vascular surgery. Lab Anim Sci 1981, 31(3):263-267.

20. Foley SR, Solano C, Simonova G, Spanevello MM, Bird RJ, Semple JW, Jackson DE, SchiblerA, Fraser JF, Fung YL: A comprehensive study of ovine haemostasis to assess suitability to model human coagulation. Thromb Res 2014, 134(2):468-473.

21. Standring S (editor-in-chief): Vascular supply and drainage of the brain. In: Gray’s Anatomy. The anatomical basis of clinical practice. 40th ed. Edinburgh, Scotland, UK: Churchill Livingstone Elsevier; 2008, 446-460.

22. Kapoor K, Singh B, Dewan J: Variations in the confi guration of the circle of Willis. Anat Sci Int 2008, 83(2): 96-106.

23. Boorder M, van der Grond J, van Dongen AJ, Klijn CJ, Jaap Kappelle L et al: Spect measurements of regional cerebral perfusion and carbondioxide reactivity: Correlation with cerebral collaterals in internal carotid artery occlusive disease. J Neurol 2006, 253(10):1285-1291.

24. Purves MJ: Some aspects of the anatomy of cerebral blood vessels. In: The physiology of the cerebral circulation. Cambridge, UK: Cambridge University Press; 1972, 1-10, 69-100, 156-172.

25. Grau H: Der Kreislaufapparat In: Ellenberger W, Baum H: Handbuch der vergleichenden Anatomie der Haustiere. 18th ed. Berlin, Germany: Springer-Verlag; 1943, 629-644, 662-669.

26. I.C.V.G.A.N: Angiologia. In: Nomina Anatomica Veterinaria. 5th ed. Hannover, Columbia, Gent, Sapporo: Editorial Committee I.C.V.G.A.N; 2005, 78-85.

27. Waibl H, Sinowatz F: Kreislaufapparat und Lymphatisches System. In: Nickel R, Schummer A, Seiferle E: Lehrbuch der Anatomie der Haustiere Band III - Kreislaufsystem, Haut und Hautorgane. 4th ed. Stuttgard, Germany: Parey Verlag; 2004, 104-120.

28. Baldwin BA, Be ll FR: Blood fl ow in the carotid and vertebral arteries of the sheep and calf. J Physiol 1963, 167:448-462.

29. Baldwin BA, Bell FR: The anatomy of the cerebral circulation of the sheep and ox. The dynamic distribution of the blood supplied by the carotid and vertebral arteries to cranial regions. J Anat 1963, 97(2):203-215.

30. May NDS: Arterial anatomoses in the head and neck of the sheep. J Anat 1967, 101(2):381-387.

31. May NDS: Experimental studies of the collateral circulation in the head and neck of sheep (Ovis aries). J Anat 1968, 103(1):171-181.

32. Guyton A, Hall J: Cerebral blood fl ow, the cerebrospinal fl uid and brain metabolism. In: Textbook of medical physiology. 11th ed. Philadelphia, Pennsylvania, USA: Elsevier Saunders; 2006, 761-770.

33. Zarrinkoob L, Ambarki K, Wahlin A, Birgander R, Eklund A, Malm J: Blood fl ow distribution in cerebral arteries. J Cereb Blood Flow Metab 2015, 35(4):648-654.

34. Hibbard L, McGlone JS, Davis DW, Hawkins RA: Three-dimensional representation and analysis of brain energy metabolism. Science 1987, 236(4809):1641-1646.

35. Casals JB, Pieri NC, Feitosa ML, Ercolin AC, Roballo KC, Barreto RS, Bressan FF, Martins DS, Miglino MA, Ambrósio CE: The use of animal models for stroke research: a review. Comp Med 2011, 61(4):305-313.

36. Graham SM, McCullough LD, Murphy SJ: Animal models of ischemic stroke: Balancing experimental aims and animal care. Comparative Med 2004, 54(5):486-496.

37. Hossmann KA: An imal models of cerebral ischemia. 1 Review of literature. Cerebrovasc Dis 1991, 1(Suppl 1):2-15.

38. Traystman RJ: Animal models of focal and global cerebral ischemia. ILAR J 2003, 44(2):85-95.

39. Förschler A, Boltze J, Waldmin D, Gille U, Zimmer C: MRI of experimental focal cerebral ischemia in sheep. Rofo 2007, 179(5):516-524.

40. Terlecki S, Baldwin BA, Bell FR: Experimental cerebral ischaemia in sheep. Neuropathology and clinical effects. Acta Neuropathol 1967, 7(3):185-200.

41. Wells AJ, Vink R, Blumbergs PC, Brophy BP, Helps SC, Knox SJ, Turner RJ: A surgical model of permanent and transient middle cerebral artery stroke in the sheep. PLoS One 2012, 7(7):e42157.

42. McClure M, Riddle A, Manese M, Luo NL, Rorvik DA, Kelly KA, Barlow CH, Kelly JJ, Vinecore K, Roberts C, Hohimer AR, Back SA: Cerebral blood fl ow heterogenicity in preterm sheep: Lack of physiological support for vascular boundary zones in foetal cerebral white matter. J Cereb Blood Flow Metab 2008, 28(5):995-1008.

43. Shaw C, Alvord E, Berry R: Swelling of the brain following ischaemic infarction with cerebral occlusion. Arch Neurol 1959 1:161-177.

44. Teraura T, Meyer J, Sakamoto K: Hemodynamic and metabolic concomitants of brain swelling and cerebral oedema due to experimental infarction. J Neurosurg 1972, 36 (6):728-744.

45. Pearce JMS: Historical note on carotid disease and ligation. Eur Neurol 2014, 72(1-2):26-29.

46. Robicsek F, Roush TS, Cook JW, Reames MK: From Hippocrates to Palmaz-Schatz, the history of carotid surgery. Eur J Vasc Endovasc Surg 2004, 27 (4):389-397.

47. Thompson JE: Carotid surgery: The past is prologue. J Vasc Surg 1997, 25 (1):131-140.

48. Coley RW: Case of rupture o f the carotid artery and wounds of several of its branches, successfully treated by tying the common trunk of the carotid itself. Med Chir J Rev 1817, 3:1-4.

49. Thompson JE: The evolution of surgery for the treatment and prevention of stroke. The Willis lecture. Stroke 1996, 27(8):1427-1434.

50. Cooper A: A case of aneurysm of the carotid artery. Med Chir Trans 1809, 1:1-12.

51. Okamoto Y, Inugami A, Matzuzaki Z, Yokomizo M, Konno A, Togawa K, Kuribayashi R, Ogawa T, Kanno I: Carotid artery resection for head and neck cancer. Surgery 1996, 120(1):54-59.

52. Konno A, Togawa K Lizuka K: Analysis of factors affecting complications of carotid ligation. Ann Otol Rhinol Laryngol 1981, 90(3):222-226.

53. Kroeker TR, O’Brien JC: Carotid resection and reconstruction associated with treatment of head and neck cancer. Proc (Bayl Univ Med Cent) 2011, 24(4):295-298.

54. Winn HR, Richardson AE, Jane JA: Late morbidity and mortality of common carotid ligation for posterior communicating aneurysms. A comparison to conservative treatment. J Neurosurg 1977, 47(5):727-736.

55. Lilienthal D.: Ligation of both common carotids. Ann Surg 1903, 37(3):443-444.

56. Catlin D: A case of carcinoma of the larynx survival bilateral carotid artery ligation. Ann Surg 1960, 152 (5): 809-814.

57. Linzell JL, Waites GM: The effects of oc cluding the carotid and vertebral arteries in sheep and goats. J Physiol 1957, 1 38:P20.

58. Baldwin BA, Bell FR: The effect of temporary reduction in cephalic blood fl ow on the EEG of sheep and calf. Electroencephalogr Clin Neurophysiol 1963, 15(3):465-473.

59. Baldwin BA, Bell FR: The effect on blood pressure in the sheep and calf of clamping some of the arteries contributing to cephalic circulation. J Physiol 1963, 167:463-479.

60. Waites GM: The infl uence of the occipito-vertebral anastomoses on the carotid sinus refl ex of the sheep. Q J Exp Physiol Cogn Med Sci 1960, 45(3):243-251.

61. Andersson B, Jew ell PA: The distribution of carotid and vertebral blood in the brain and spinal cord of the goat. Q J Exp Physiol C ogn Med Sci 1956, 41(4):462-474.

62. Bhattacharjee AK, White L, Chang L, Ma K, Harry GJ, Deutsch J, Rapoport SI: Bilateral common carotid artery ligation transiently changes brain lipid metabolism in rats. Neurochem Res 2012, 37(7):1490-1498.

63. Bunce D: Survival of dogs following section of carotid and vertebral arteries. Proc Soc Exp Biol Med 1960, 103:581-585.

64. Cho JN, Kim SH, Kim KT, Kim Y: Clinical and pathological study after ligation of common carotid artery in the rat. J Korean Neurosurg Soc 1991, 20(12):1069-1075.

65. Chungcharoen D, De Burgh DM, Neil E, Schweitzer A: The effect of carotid occlusion upon the intrasinusal pressure with special reference to vascular communications between the carotid and vertebral circulations in the dog, cat and rabbit. J Physiol 1952, 117(1):56-76.

66. Clendenin MA, Conrad MD: Collateral vessel development after chronic bilateral common carotid artery occlusion in dog. Am J Vet Res 1979, 40(9):1244-1249.

67. Eseoglu M, Yilmaz I, Karalar M, Aydin MD, Kayaci S, Gundogdu C, Gunaldi O, Onen MR: The role of sympa thectomy on the regulation of basilar artery volume changes in stenoocclusive carotid artery modelling after bilateral common carotid artery ligation: an animal model. Acta Neurochir (Wien) 2014, 156(5):963-969.

68. Farkas E, Luiten PG, Bari F: Permanent bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 2007, 54(1):162-180.

69. Huang Y, Fan S, Li J, Wang YL: Bilateral common carotid artery occlusion in the rat as a model of retinal ischaemia. Neuroophthalmology 2014, 38(4):180-188.

70. Lavinsky D, Arterni NS, Achval M, Netto CA: Chronic bilateral common carotid artery occlusion: a model for ocular ischemic syndrome in the rat. Graefes Arch Clin Exp Ophthalmol 2006, 244(2):199-204.

71. Melo MCSC, Gadelh a D, Mascena GV, Oliveira TK, Brandt CT: Learning and surv ival undergoing a permanent bilateral carotid ligation in rats. Acta Cir Bras 201 3, 28(2):102-105.

72. Ohta H, Nishikawa H, Kimura H, Anayama H, Moyamoto M: Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats. Neuroscience 1997, 79(4):1039-1050.

73. Oldendorf WH: Trophic changes in the arteries at the base of the rat brain in response to bilateral common carotid artery ligation. J Neuropathol Exp Neurol 1989, 48(5):534-547.

74. Payan HM: Ill-effects of carotid artery ligation: Experimental study on infl uence of age. Ann Surg 1967, 165(4):544-550.

75. Sarti C, Pantoni L, Bartolini L, Inzitari D: Persistent impairment of gait performances and working memory after bilateral common carotid artery occlusion in the adult Wistar rat. Behav Brain Res 2002, 136(1):13-20.

76. Sengupta D, Harper M, Jennet B: Effect of carotid ligation on blood fl ow in baboons. 2. Response to hypoxia and haemorrhagic hypertension. J Neurol Neurosurg Psychiatry 1974, 37(5):578-584.

77. Chen L, Shang Y, Sipos E, Saatman KE, Yu G, Toborek M: Novel experimental model for repeated forebrain ischemia-reperfusion. J Exp Stroke Transl Med 2012, 5(1):1-10.

78. Jha AN, Butler P, Lye RH, Fawcitt RA: Carotid ligation: what happens in the long term? J Neurol Neurosurg Psychiatry 1986, 49(8):893-898.

79. Yashon D, Johnson AB, Jane JA: Bilateral internal carotid artery occlusion secondary to closed head injuries. J Neurol Neurosurg Psychiatry 1964, 27:547-552.

80. Maves MD, Bruns MD, Keenan MJ: Carotid artery resection for head and neck cancer. Ann Otol Rhinol Laryngol 1992, 101(9):778-781.

81. Enzler M, Zünd G, Schneider J: A new approach to in vivo testing of vascular grafts. Vasa 1994, 23(3):251-256.

82. Giardino R, Fini M, Rocca M, Nicoli N, Martini L, Giavaresi G, Di Paola MD, Orienti L, Faggioli G, Gargiulo M: In vivo experimental research in vascular surgery. Methodology and current Italian law. Minerva Chir 1995, 50(6):613-619.

83. AVMA (American Veterinary Medical Association): Report of the AVMA. Panel on euthanasia. J Am Vet Med Assoc 1993, 202(2):229-249.

84. Louhimies S: Directive 86/609/EEC on the protection of animals used for experimental and other scientifi c purposes. ATLA-Altern Lab Anim 2002, 30 (2):217-219.

85. Hooijmans CR, de Vries R, Leenaars M, Curfs J, Ritskes-Hoitinga M: Improving planning, design, reporting and scientifi c quality of animal experiments by using the gold standard publication checklist , in addition to the ARRIVE guidelines. Brit J Pharmacol 2011, 162:1259-1260.

86. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010, 8 (6):1-5. e1000412.

87. Trollope A, Moxon JV, Moran CS, Golledge J: Animal models of abdominal aortic aneurysm and their role in furthering management of human disease. Cardiovasc Pathol 2011, 20(2):114-123.

88. Jackson SJ, Andrews N, Ball D, Bellantuono I, Gray J, Hachoumi L, Holmes A, Latcham J, Petrie A, Potter P, Rice A, Ritchie A, Stewart M, Strepka C, Yeoman M, Chapman K: Does age matter? The impact of rodent age on study outcomes. Lab Anim 2016, [Epub ahead of print].

89. B aldwin BA: T he anatomy of the arterial supply of the cranial regions of the sheep and ox. Am J Anat 1964, 115 (1):101-118.

90. Daniel PM, Dawes JDK, Prichard MML: Studies of the carotid rete and its associated arteries. Philos Trans R Soc Lond (Biol) 1953, 237: 173-208.

91. Kapoor K, Kak VK, Singh B: Morphology and comparative anatomy of circulus arteriosus cerebri in mammals. Anat Histol Embryol 2003, 32(6):347-355.

92. Kapoor K, Singh B, Dewan LI: Variations in the confi guration of the circle of Willis. Anat Sci Int 2008, 83 (2):96-106.

93. Deepthi S, Suseelamma D, Pramod Kumar D, Saradadevi SS, Subhadradevi V: Comparative study of formation of circle of Willis in human and sheep brain. J Anat Soc India 2016, 65 (Suppl 1):S16-S19.

94. Itoyama Y, Kitano I, Ushio Y: Carotid and vertebral rete mirabile in man - case report. Neurol Med Chir (Tokyo) 1993, 33:181-184.

95. Whisnant JP, Millikan CH, Sayre GP, Wakim KH: Collateral circulation to the brain of the dog following bilateral ligation of the carotid and vertebral arteries. Am J Physiol 1956, 186 (2):275-277.

96. Kaste M: Use of animal models has not contributed to development of acute stroke therapies. Stoke 2005, 36(10):2323-2324.

97. Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I: Where is the evidence that animal research benefi ts humans? BMJ 2004, 328(7438):514-517.

98. Bracken MB: Why animal studies are often poor predictors of human reactions to exposure. J R Soc Med 2009, 102(3):120-122.

99. Gold H: The proper study of mankind is the man. Am J Med 1952, 12(6):619-620.

100. Hackam DG, Redelmeier DA: Translation of research evidence from animals to humans. JAMA 2006, 296 (14):1731-1732.

101. Matthews RAJ: Medical progress depends on animal models - doesn’t it? J Royal Soc Med 2008, 101(2):95-98.

102. Mignini LE, Khan KS: Methodological quality of systematic reviews of animal studies: a survey of reviews of basic research. BMC Med Res Methodol 2006, 6:10.

103. Newhook JC, Blackmore DK: Electroencephalographic studies of stunning and slaughter of sheep and calves - part 1: The onset of permanent insensibility in sheep during slaughter. Meat Sci 1982, 6 (3):221-233.

104. Nangeroni LI, Kennett PD: The study of the effects of Shechita slaughter on the sheep (Ovis aries). In: An electroencephalographic study of the effect of Shechita slaughter on cortical function in ruminants. New York, USA: Department of Physiology - Veterinary College - Cornell University 1963, 1-17.

105. Rosen SD: Physiological insights into Shechita. Vet Rec 2004, 154 (24):759-765.

106. Daly CC, Kallweit E, Ellendorf F: Cortical function in cattle during slaughter: conventional captive bolt stunning followed by exsanguinations compared with Shechita slaughter. Vet Rec 1988, 325-329.

107. Daly CC, Whittington P: Concussive methods of pre-slaughter stunning in sheep: effects of captive bolt stunning in the poll position on brain function. Res Vet Sci 1986, 41 (3):353-355.

108. Daly CC, Whittington PE: Investigation into the principal determinants of effective captive bolt stunning of sheep. Res Vet Sci 1989, 46 (3):406-408.

109. Rodriguez P, Velarde A, Dalmau A, Llonch P: Assessment of unconsciousness during slaughter without stunning in lambs. Anim Welf 2012, 21 (S2):75-80.

110. Fuseini A, Wotton SB, Hadley PJ, Knowles TG: The perception and acceptability of preslaughter stunning for Halal production: The views of UK Islamic scholars and Halal consumers. Meat Sci 2017, 123:143-150.

Acta Veterinaria

The Journal of University of Belgrade

Journal Information

IMPACT FACTOR 2018: 0.656
5-year IMPACT FACTOR: 0,532

CiteScore 2018: 0.71

SCImago Journal Rank (SJR) 2018: 0.281
Source Normalized Impact per Paper (SNIP) 2018: 0.547


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 356 281 14
PDF Downloads 154 129 6