Increased perfusion pressure enhances the expression of endothelin (ETB) and angiotensin II (AT1) receptors in rat basilar artery smooth muscle cells

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Isak Lindstedt Pär Bengtsson Marie-Louise Edvinsson Lars Edvinsson



It is known that the endothelin and angiotensin receptors ETA/ETB and AT1 on smooth muscle cells induce contraction and stimulate proliferation and cell hypertrophy. In hypertensive animals and in situations of altered blood flow, e.g. in stroke, there is an up-regulation of ET- and AT-receptors due to de novo transcription. In order to simulate this situation we hypothesized that changes in perfusion pressure may result in altered expression of protein encoding for the receptors ETA, ETB, AT1, and AT2 in the rat basilar artery.


Segments of the rat basilar artery (n = 6) were cannulated with glass micropipettes, pressurized and luminally perfused in a perfusion chamber. After exposure to normal (80/70 mm Hg) or high (140/130 mm Hg) pressure at constant flow for 16 hours the vessel segments were immersed in a fixative solution, dehydrated, frozen, cut in a cryostat and immunohistology-stained for ET- and AT-receptor protein.


ETB- and AT1-receptor proteins were significantly up-regulated after high perfusion pressure compared to normal perfusion pressure at 16 hours (p < 0.05). Immunohistochemistry showed that the up-regulated proteins were located mainly in the smooth muscle cells in the arterial wall.


The results from our rat perfusion model show significant up-regulation of ETB- and AT1-receptor proteins after high perfusion pressure. Since the increased protein expression was located in the smooth muscle layer, the results of our study have suggested a shift in the role of the endothelin and angiotensin system towards a worsening of the pathophysiology in the early stages of hypertension.

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LINDSTEDT, Isak et al. Increased perfusion pressure enhances the expression of endothelin (ETB) and angiotensin II (AT1) receptors in rat basilar artery smooth muscle cells. Medical Research Archives, [S.l.], v. 6, n. 2, feb. 2018. ISSN 2375-1924. Available at: <>. Date accessed: 28 nov. 2021. doi:
Research Articles


1. Schiffrin EL. Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens 2001; 14: 83S-89S.
2. Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S, et al. Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension 1997; 30: 29–34.
3. Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, et al. Endothelin. Pharmacol Rev 2016; 68(2):357-418.
4. Wagenaar LJ, Voors AA, Buikema H, van GilstWH. Angiotensin receptors in the cardiovascular system. Can J Cardiol 2002; 18(12): 1331-9.
5. Lauth M, Berger M, Cattaruzza M, Hecker M. Elevated perfusion pressure upregulates endothelin-1 and endothelin B receptor expression in the rabbit carotid artery. Hypertension 2000; 35(2): 648–654.
6. Schiffrin EL, Deng LY, Sventek P, Day R. Enhanced expression of endothelin-1 gene in endothelium of resistance arteries in severe human essential hypertension. J Hypertens 1997; 15(1): 57–63.
7. Nilsson D, Wackenfors A, Gustafsson L, Edvinsson L, Paulsson P, Ingemansson R. Increased ETA and ETB receptor contraction in the left internal mammary artery from patients with hypertension. J Human Hypertens 2008; 22(3): 226-229.
8. Li J, Cao YX, Liu H, Xu CB. Enhanced G-protein coupled receptors-mediated contraction and reduced endothelium-dependent relaxation in hypertension. Eur J Pharmacol 2007; 557(2-3): 186–194.
9. Dagassan PH, Breu V, Clozel M, Künzli A, Vogt P, Turina M, et al. Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries. J CardiovascPharmacol 1996; 27(1): 147–53.
10. Katugampola SD, Davenport AP. Changes in ETA-, AT1- and AT2-receptors in the phenotypically transformed intimal smooth muscle layer of human atherosclerotic coronary arteries. J CardiovascPharmacol 2000; 36: S395-S396.
11. Cannan CR, Burnett JC, Lerman A. Enhanced coronary vasoconstriction to endothelin-B-receptor activation in experimental congestive heart failure. Circulation 1996; 93(4): 646–651.
12. Wackenfors A, Emilson M, Ingemansson R, Hortobagyi T, Szok D, Tajti J. Ischemic heart disease induce upregulation of endothelin receptor mRNA in human coronary arteries. Eur J Pharmacol 2004; 484(1): 103-109.
13. Hansen-Schwarts J, Hoel NL, Zhou M, Xu CB, Svendgaard NA, Edvinsson L. Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 2003; 52(5): 1188-94.
14. Stenman E, Malmsjo M, Uddman E, Gidö G, Wieloch T, Edvinsson L. Cerebral ischemia upregulates vascular endothelin ET (B) receptors in rat. Stroke 2002; 33(9): 2311–2316.
15. Maddahi A, Edvinsson L. Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway. BMC Neuroscience 2008; 9:85.
16. Diniz C, Leal S, Logan K, Rocha-Pereira C, Soares AS, Rocha E. Immunohistochemical localization of angiotensin II receptor types 1 and 2 in the mesenteric artery from spontaneously hypertensive rats. Microsc Res Tech 2007; 70(8): 677-81.
17. Wackenfors A, Pantev E, Emilson M, Edvinsson L, Malmsjo M. Angiotensin II receptor mRNA expression and vasoconstriction in human coronary arteries: effects of heart failure and age. Basic ClinpharmacolToxicol 2004; 95(6): 266–272.
18. Wackenfors A, Emilson M, Ingemansson R, Edvinsson L, Malmsjo M. Ischemic heart disease down-regulates angiotensin type 1 receptor mRNA in human coronary arteries. Eur J Pharmacol 2004; 503(1-3): 147–153.
19. Lindstedt I, Xu CB, Zhang Y, Edvinsson L. Increased perfusion pressure enhances the expression of endothelin (ETB) and angiotensin II (AT1, AT2) receptors in rat mesenteric artery smooth muscle cells. Blood Pressure, 2009; 18(1-2): 78–85.
20. Li J, Cao YX, Liu Y, Xu CB. Minimally modified LDL upregulates endothelin type B receptors in rat basilar artery. Microvasc Res 2012; 83(2): 178-184.
21. de Andrade CR, Leite PF, Montezano AC, et al. Increased endothelin-1 reactivity and endothelial dysfunction in carotid arteries from rats with hyperhomocysteinemia. Br J Pharmacol 2009; 157(4): 568-80.
22. Morawietz H, Talanow R, Szibor M, Rueckschloss U, Schubert A, Bartling B, et al. Regulation of the endothelin system by shear stress in human endothelial cells. J Physiology 2000; 523(3)761–770.
23. Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Pressure enhances endothelin-1 release from cultured human endothelial cells. Hypertension 1995; 25(3): 449–452.
24. Macarthur H, Warner TD, Wood EG, Corder R, Vane JR. Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch. BiochemBiophys Res Commun 1994; 200(1): 395–400.
25. Wang DL, Wung BS, Peng YC, Wang JJ. Mechanical strain increases endothelin-1 gene expression via protein kinase C pathway in human endothelial cells. J Cell Physiol 1995; 163(2): 400–406.
26. Cattaruzza M, Eberhardt I, Hecker M. Mechanosensitive transcription factors involved in endothelium B receptor expression. J BiolChem 2001; 276(40): 36999–37003.
27. Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol 1993; 264: H150–H156.
28. Ramkhelawon B, Vilar J, Rivas D, Mees B, de Crom R, Tedgui A, et al. Shear stress regulates angiotensin type 1 receptor expression in endothelial cells. Circ Res. 2009;105(9):869-875.