Abstract
Interstitial cells of Cajal are believed to play an important role in gastrointestinal tissues by generating and propagating electrical slow waves to gastrointestinal muscles and/or mediating signals from the enteric nervous system. Recently cells with similar morphological characteristics have been found in the wall of blood vessels such as rabbit portal vein and guinea pig mesenteric artery. These non‐contractile cells are characterised by the presence of numerous processes and were easily detected in the wall of the rabbit portal vein by staining with methylene blue or by antibodies to the marker of Interstitial Cells of Cajal c‐kit. These vascular cells have been termed “interstitial cells” by analogy with interstitial cells found in the gastrointestinal tract. Freshly dispersed interstitial cells from rabbit portal vein and guinea pig mesenteric artery displayed various Ca2+‐release events from endo/sarcoplasmic reticulum including fast localised Ca2+ transients (Ca2+ sparks) and longer and slower Ca2+ events. Single interstitial cells from the rabbit portal vein, which is a spontaneously active vessel, also demonstrated rhythmical Ca2+ oscillations associated with membrane depolarisations, which suggests that in this vessel interstitial cells may act as pacemakers for smooth muscle cells. The function of interstitial cells from the mesenteric arteries is yet unknown. This article reviews some of the recent findings regarding interstitial cells from blood vessels obtained by our laboratory using electron microscopy, immunohistochemistry, tight‐seal patch‐clamp recording, and fluorescence confocal imaging techniques.
Keywords: Interstitial Cells of Cajal, smooth muscle cells, rabbit portal vein, guinea pig mesenteric artery, rhythmical Ca2+ waves
References
- 1. Cajal SR. El plexo de Auerbach de los batracios. Nota sobre el plexo de Auerbach de la rana. Trab Lab Histol. Fac. Med. (Barc.) 1892; 23–8. [Google Scholar]
- 2. Thuneberg L. One hundred years of interstitial cells of Cajal. Microsc. Res. Tech. 1999; 47: 223–38. [DOI] [PubMed] [Google Scholar]
- 3. Faussone Pellegrini MS, Cortesini C, Romagnoli P. Ultrastructure of the tunica muscularis of the cardial portion of the human esophagus and stomach, with special reference to the so‐called Cajal's interstitial cells. Arch. Ital. Anat. Embriol. 1977; 82: 157–77. [PubMed] [Google Scholar]
- 4. Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells' Adv. Anat. Embryol. Cell Biol. 1982; 71: 1–130. [PubMed] [Google Scholar]
- 5. Thuneberg L, Rumessen JJ, Mikkelsen HB. Interstitial cells of Cajal ‐ an intestinal impulse generation and conduction system' Scand. J Gastroenterol Suppl. 1982; 71: 143–4. [PubMed] [Google Scholar]
- 6. Sanders KM. A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 1996; 111:492–515. [DOI] [PubMed] [Google Scholar]
- 7. Sanders KM, Ordog T, Koh SD, Torihashi S, Ward SM. Development and plasticity of interstitial cells of Cajal. Neurogastroenterol Motil. 1999; 11:311–38. [DOI] [PubMed] [Google Scholar]
- 8. Daniel EE, Posey‐Daniel V. Neuromuscular structures in opossum esophagus: role of interstitial cells of Cajal. Am J Physiol. 1984; 246:G305–15. [DOI] [PubMed] [Google Scholar]
- 9. Young HM, Ciampoli D, Southwell BR, Newgreen DF. Origin of interstitial cells of Cajal in the mouse intestine. Dev Biol. 1996; 180: 97–107. [DOI] [PubMed] [Google Scholar]
- 10. Lecoin L, Gabella G, Le Douarin N. Origin of the c‐kit‐positive interstitial cells in the avian bowel. Development 1996; 122: 725–33. [DOI] [PubMed] [Google Scholar]
- 11. Torihashi S, Gerthoffer WT, Kobayashi S, Sanders KM. Identification and classification of interstitial cells in the canine proximal colon by ultrastructure and immunocytochemistry. Histochemistry 1994; 101: 169–83. [DOI] [PubMed] [Google Scholar]
- 12. Torihashi S, Nishi K, Tokutomi Y, Nishi T, Ward S, Sanders KM. Blockade of kit signaling induces transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotype. Gastroenterology 1999; 117: 140–8. [DOI] [PubMed] [Google Scholar]
- 13. Sergeant GP, Hollywood MA, McHale NG, Thornbury KD. Spontaneous Ca2+ activated Cl‐ currents in isolated urethral smooth muscle cells. J Urol. 2001; 166: 1161–6. [PubMed] [Google Scholar]
- 14. Sergeant GP, Hollywood MA, McCloskey KD, Thornbury KD, McHale NG. Specialised pacemaking cells in the rabbit urethra. J Physiol. 2000; 526: 359–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. McCloskey KD, Gurney AM. Kit positive cells in the guinea pig bladder. J Urol. 2002; 168: 832–6. [PubMed] [Google Scholar]
- 16. Burton LD, Housley GD, Salih SG, Jarlebark L, Christie DL, Greenwood D. P2X2 receptor expression by interstitial cells of Cajal in vas deferens implicated in semen emission. Auton Neurosci. 2000; 84:147–61. [DOI] [PubMed] [Google Scholar]
- 17. Rumessen JJ, de Kerchove d'Exaerde A, Mignon S, Bernex F, Timmermans JP, Schiffmann SN, Panthier JJ, Vanderwinden JM. Interstitial cells of Cajal in the striated musculature of the mouse esophagus. Cell Tissue Res. 2001; 306: 1–14. [DOI] [PubMed] [Google Scholar]
- 18. Exintaris B, Klemm MF, Lang RJ. Spontaneous slow wave and contractile activity of the guinea pig prostate. J Urol. 2002; 168: 315–22. [PubMed] [Google Scholar]
- 19. van den Aa F, Roskams T, Blyweert W, de Ridder D. Interstitial cells in the human prostate: a new therapeutic target' Prostate 2003; 56: 250–5. [DOI] [PubMed] [Google Scholar]
- 20. Hashitani H, Suzuki H. Identification of interstitial cells of Cajal in corporal tissues of the guinea‐pig penis. Br J Pharmacol. 2004; 141: 199–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. McCloskey KD, Hollywood MA, Thornbury KD, Ward SM, McHale NG. Kit‐like immunopositive cells in sheep mesenteric lymphatic vessels. Cell Tissue Res. 2002; 310:77–84. [DOI] [PubMed] [Google Scholar]
- 22. Duquette RA, Shmygol A, Vaillant C, Mobasheri A, Pope M, Burdyga T, Wray S. Vimentin‐positive, c‐kit‐negative interstitial cells in human and rat uterus: a role in pacemaking' Biol Reprod. 2005; 72: 276–83. [DOI] [PubMed] [Google Scholar]
- 23. Popescu LM, Hinescu ME, Ionescu N, Ciontea SM, Cretoiu D, Ardelean C. Interstitial cells of Cajal in pancreas. J Cell Mol Med. 2005; 9: 169–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Povstyan OV, Gordienko DV, Harhun MI, Bolton TB. Identification of interstitial cells of Cajal in the rabbit portal vein. Cell Calcium 2003; 33: 223–39. [DOI] [PubMed] [Google Scholar]
- 25. Pucovsky V, Moss RF, Bolton TB. Non‐contractile cells with thin processes resembling interstitial cells of Cajal found in the wall of guinea‐pig mesenteric arteries. J Physiol. 2003; 552: 119–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Harhun MI, Gordienko DV, Povstyan OV, Moss RF, Bolton TB. Function of interstitial cells of cajal in the rabbit portal vein. Circ Res. 2004; 95:619–26. [DOI] [PubMed] [Google Scholar]
- 27. Povstyan OV, Harhun MI, Bolton TB. Interstitial cells of Cajal in the wall of mouse mesenteric artery. J Physiol Biochem. 2005; 61:72. [Google Scholar]
- 28. Dahl E., Nelson E. Electron microscopic observation on human intracranial arteries II. Innervation. Arch Neurol. 1964; 10: 158–64. [DOI] [PubMed] [Google Scholar]
- 29. Lee RM. Morphology of cerebral arteries. Pharmacol. Ther. 1995; 66: 149–73. [DOI] [PubMed] [Google Scholar]
- 30. Harhun MI, Gordienko DV, Povstyan OV, Bolton TB. Rhythmical [Ca2+]i oscillations linked to slow wave generation in single vascular interstitial cells of Cajal. Biophys J. 2004; 86: 113–4. [Google Scholar]
- 31. Bolton TB, Gordienko DV, Povstyan OV, Harhun MI, Pucovsky V. Smooth muscle cells and interstitial cells of blood vessels. Cell Calcium 2004; 35: 643–57. [DOI] [PubMed] [Google Scholar]
- 32. Komuro T, Burnstock G. The fine structure of smooth muscle cells and their relationship to connective tissue in the rabbit portal vein. Cell Tissue Res. 1980; 210:257–67. [DOI] [PubMed] [Google Scholar]
- 33. Sutter MC. The mesenteric‐portal vein in research. Pharmacol Rev. 1990; 42: 287–325. [PubMed] [Google Scholar]
- 34. Harhun MI, Gordienko DV, Moss RF, Bolton TB. Rhythmical [Ca2+]i oscillations in interstitial cells of Cajal from rabbit portal vein depend on both RyRs and IP3Rs, Biophys J. 2005; 88: 440a. [Google Scholar]
- 35. Huizinga JD, Robinson TL, Thomsen L. The search for the origin of rhythmicity in intestinal contraction; from tissue to single cells. Neurogastroenterol Motil. 2000; 12: 3–9. [DOI] [PubMed] [Google Scholar]
- 36. Hirst GD, Ward S M. Interstitial cells: involvement in rhythmicity and neural control of gut smooth muscle. J Physiol. 2003; 550: 337–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Povstyan O, Gordienko DV, Harhun MI, Bolton TB. ICC‐like cell type in rabbit portal vein. Biophys J. 2002; 82: 417. [Google Scholar]
- 38. Harhun MI, Gordienko DV, Povstyan OV, Bolton TB. Intercommunication between interstitial cells (ICs) and smooth muscle cells (SMCs) from rabbit portal vein' Biophys J. 2003; 84: 105a. [Google Scholar]
- 39. Langton P, Ward SM, Carl A, Norell MA, Sanders KM. Spontaneous electrical activity of interstitial cells of Cajal isolated from canine proximal colon. Proc Natl Acad Sci USA. 1989; 86:7280–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Thomsen L, Robinson TL, Lee JC, Farraway LA, Hughes MJ, Andrews DW, Huizinga JD. Interstitial cells of Cajal generate a rhythmic pacemaker current. Nat Med. 1998; 4: 848–51. [DOI] [PubMed] [Google Scholar]
- 41. Koh SD, Sanders KM, Ward SM. Spontaneous electrical rhythmicity in cultured interstitial cells of cajal from the murine small intestine. J Physiol. 1998; 513: 203–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Lee JC, Thuneberg L, Berezin I, Huizinga JD. Generation of slow waves in membrane potential is an intrinsic property of interstitial cells of Cajal. Am J Physiol. 1999; 277: G409–23. [DOI] [PubMed] [Google Scholar]
- 43. Gordienko DV, Greenwood IA, Bolton TB. Direct visualization of sarcoplasmic reticulum regions discharging Ca2+ sparks in vascular myocytes. Cell Calcium 2001; 29: 13–28. [DOI] [PubMed] [Google Scholar]
- 44. Gordienko DV, Bolton TB. Crosstalk between ryanodine receptors and IP3 receptors as a factor shaping spontaneous Ca2+‐release events in rabbit portal vein myocytes. J Physiol 2002; 542: 743–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Bolton TB, Gordienko DV, Pucovsky V, Parsons S, Povstyan O. Calcium release events in excitation‐contraction coupling in smooth muscle. Novartis Found Symp. 2002; 246: 154–68. [DOI] [PubMed] [Google Scholar]
- 46. Bolton TB, Gordienko DV, Pucovsky V, Povstyan OV, Harhun MI, Parsons SP. Calcium Events in Smooth Muscles and Their Associated Cells. Neurophysiology 2003; 35: 155–60. [Google Scholar]
- 47. Publicover NG, Horowitz NN, Sanders KM. Calcium oscillations in freshly dispersed and cultured interstitial cells from canine colon. Am J Physiol. 1992; 262: C589–97. [DOI] [PubMed] [Google Scholar]
- 48. Ward SM, Ordog T, Koh SD, Baker SA, Jun JY, Amberg G, Monaghan K, Sanders KM. Pacemaking in interstitial cells of Cajal depends upon calcium handling by endoplasmic reticulum and mitochondria. J Physiol. 2000; 525: 355–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Malysz J, Donnelly G, Huizinga JD. Regulation of slow wave frequency by IP3‐sensitive calcium release in the murine small intestine. Am J Physiol Gastrointest Liver Physiol. 2001; 280: G439–48. [DOI] [PubMed] [Google Scholar]
- 50. Rich A, Hanani M, Ermilov LG, Malysz J, Belzer V, Szurszewski JH, Farrugia G. Physiological study of interstitial cells of Cajal identified by vital staining. Neurogastroenterol Motil. 2002; 14: 189–96. [DOI] [PubMed] [Google Scholar]
- 51. Torihashi S, Fujimoto T, Trost C, Nakayama S. Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae. J Biol Chem. 2002; 277: 19191–7. [DOI] [PubMed] [Google Scholar]
- 52. Holman ME, Kasby CB, Suthers MB, Wilson JA. Some properties of the smooth muscle of rabbit portal vein. J Physiol. 1968; 196: 111–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Tokutomi N, Maeda H, Tokutomi Y, Sato D, Sugita M, Nishikawa S, Nishikawa S, Nakao J, Imamura T, Nishi K. Rhythmic Cl‐ current and physiological roles of the intestinal c‐kit‐positive cells. Pflugers Arch. 1995; 431: 169–77. [DOI] [PubMed] [Google Scholar]
- 54. Huizinga JD, Zhu Y, Ye J, Molleman A. High‐conductance chloride channels generate pacemaker currents in interstitial cells of Cajal. Gastroenterology 2002; 123: 1627–36. [DOI] [PubMed] [Google Scholar]
- 55. Hirst GD, Bramich NJ, Teramoto N, Suzuki H, Edwards FR. Regenerative component of slow waves in the guinea‐pig gastric antrum involves a delayed increase in [Ca2+]i and Cl‐channels. J Physiol. 2002; 540: 907–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Koh SD, Jun JY, Kim TW, Sanders KM. A Ca2+‐inhibited non‐selective cation conductance contributes to pacemaker currents in mouse interstitial cell of Cajal. J Physiol. 2002; 540: 803–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Dickens EJ, Hirst GD, Tomita T. Identification of rhythmically active cells in guinea‐pig stomach. J Physiol. 1999; 514: 515–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Sergeant GP, Hollywood MA, McCloskey KD, McHale NG, Thornbury KD. Role of IP3 in modulation of spontaneous activity in pacemaker cells of rabbit urethra. Am J Physiol Cell Physiol. 2001; 280:C1349–56. [DOI] [PubMed] [Google Scholar]
- 59. Ward SM, Baker SA, Faoite Ad A, Sanders KM. Propagation of slow waves requires IP3 receptors and mitochondrial Ca2+ uptake in canine colonic muscles. J Physiol. 2003; 549: 207–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60. Aoyama M, Yamada A, Wang J, Ohya S, Furuzono S, Goto T, Hotta S, Ito Y, Matsubara T, Shimokata K, Chen SR, Imaizumi Y, Nakayama S. Requirement of ryanodine receptors for pacemaker Ca2+ activity in ICC and HEK293 cells. J Cell Sci. 2004; 117: 2813–25. [DOI] [PubMed] [Google Scholar]
- 61. Rumessen JJ, Thuneberg L, Mikkelsen HB. Plexus muscularis profundus and associated interstitial cells. II. Ultrastructural studies of mouse small intestine. Anat Rec. 1982; 203: 129–46. [DOI] [PubMed] [Google Scholar]
- 62. Greenwood IA, Prestwich SA. Characteristics of hyperpolarization‐ activated cation currents in portal vein smooth muscle cells. Am J Physiol Cell Physiol. 2002; 282: C744–53. [DOI] [PubMed] [Google Scholar]
- 63. Hermsmeyer K. Multiple pacemaker sites in spontaneously active vascular muscle. Circ Res. 1973; 33: 244–51. [DOI] [PubMed] [Google Scholar]
- 64. Ishikawa K, Komuro T, Hirota S, Kitamura Y. Ultrastructural identification of the c‐kit‐expressing interstitial cells in the rat stomach: a comparison of control and Ws/Ws mutant rats. Cell Tissue Res. 1997; 289: 137–43. [DOI] [PubMed] [Google Scholar]
- 65. Ward SM, Burns AJ, Torihashi S, Sanders KM. Mutation of the proto‐oncogene c‐kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol. 1994; 480: 91–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Linnekin D. Early signaling pathways activated by c‐Kit in hematopoietic cells. Int J Biochem Cell Biol. 1999; 31:1053–74. [DOI] [PubMed] [Google Scholar]
- 67. Ashman LK. The biology of stem cell factor and its receptor C‐kit. Int J Biochem Cell Biol. 1999; 31: 1037–51. [DOI] [PubMed] [Google Scholar]
- 68. Lamont C. Wier WG. Evoked and spontaneous purinergic junctional Ca2+ transients (jCaTs) in rat small arteries. Circ Res. 2002; 91: 454–6. [DOI] [PubMed] [Google Scholar]
- 69. Rumessen JJ, Vanderwinden JM. Interstitial cells in the musculature of the gastrointestinal tract: Cajal and beyond. Int Rev Cytol. 2003; 229: 115–208. [DOI] [PubMed] [Google Scholar]
- 70. Epperson A, Hatton WJ, Callaghan B, Doherty P, Walker RL, Sanders KM, Ward SM, Horowitz B. Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal. Am J Physiol Cell Physiol. 2000; 279:C529–39. [DOI] [PubMed] [Google Scholar]
- 71. Canonico B, Felici C, Papa S. CD117. J Biol Regul Homeost Agents. 2001; 15: 90–4. [PubMed] [Google Scholar]
- 72. Farrugia G, Szurszewski JH. Heme oxygenase, carbon monoxide, and interstitial cells of Cajal. Microsc Res Tech. 1999; 47: 321–4. [DOI] [PubMed] [Google Scholar]