Skip to main content
SpringerLink
Log in

The elevated expression of calcitonin receptor by cells recruited into the endothelial layer and neo-intima of atherosclerotic plaque

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Calcitonin receptor-immunoreactive (CTR-ir) endothelial and foam cells were identified in atherosclerotic plaque within the abdominal and thoracic aortas of rabbits fed a cholesterol-supplemented diet. Initially, cells within the endothelial layers of nascent atherosclerotic plaque of arteries were also CD34-positive, a marker of precursor cells of the haematopoietic lineage. In a further rabbit model with more advanced cardiovascular disease, CTR-ir cells were located deeper within the plaque as well as within the endothelial layer overlying the neo-intima. Finally, in the third model, in which the 4-week period on the atherogenic diet was followed by a 12-week period of regression on a normal chow diet, during which serum cholesterol levels returned to the normal range, CTR-ir was markedly reduced in the stabilized fibrous cap of plaque. Thus, the expression of CTR is associated with the early cellular events involved in plaque formation and is down-regulated as stabilisation of plaque progresses in the process of healing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aicher A, Rentsch M, Sasaki K-I, Ellwart JW, Fandrich F, Siebert R, Cooke JP, Dimmeler S, Heeschen C (2007) Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res 100:581–589

    Article  PubMed  CAS  Google Scholar 

  • Beamer WG, Donahue LR, Rosen CJ, Baylink DJ (1996) Genetic variability in adult bone density among inbred strains of mice. Bone 18:397–403

    Article  PubMed  CAS  Google Scholar 

  • Becskei C, Riediger T, Zund D, Wookey P, Lutz TA (2004) Immunohistochemical mapping of calcitonin receptors in the adult rat brain. Brain Res 1030:221–233

    Article  PubMed  CAS  Google Scholar 

  • Blower PJ, Puncher MR, Kettle AG, George S, Dorsch S, Leak A, Naylor LH, O’Doherty MJ (1998) Iodine-123 salmon calcitonin, an imaging agent for calcitonin receptors: synthesis, biodistribution, metabolism and dosimetry in humans. Eur J Nucl Med 25:101–108

    Article  PubMed  CAS  Google Scholar 

  • Breyer A, Estharabadi N, Oki M, Ulloa F, Nelson-Holte M, Lien L, Jiang Y (2006) Multipotent adult progenitor cell isolation and culture procedures. Exp Hematol 34:1596–1601

    Article  PubMed  CAS  Google Scholar 

  • Burgess AM (1985) The effect of calcitonin on the prechordal mesoderm, neural plate and neural crest of Xenopus embryos. J Anat 140(Pt 1):49–55

    PubMed  CAS  Google Scholar 

  • Campbell JH, Efendy JL, Han CL, Campbell GR (2000) Blood vessels from bone marrow. Ann N Y Acad Sci 902:224–229

    PubMed  CAS  Google Scholar 

  • Campbell JH, Han CL, Campbell GR (2001) Neointimal formation by circulating bone marrow cells. Ann N Y Acad Sci 947:18–24 discussion 24–5

    Article  PubMed  CAS  Google Scholar 

  • Chigurupati S, Kulkarni T, Thomas S, Shah G (2005) Calcitonin stimulates multiple stages of angiogenesis by directly acting on endothelial cells. Cancer Res 65:8519–8529

    Article  PubMed  CAS  Google Scholar 

  • Cornish J, Callon KE, Bava U, Kamona SA, Cooper GJ, Reid IR (2001) Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development. Bone 29:162–168

    Article  PubMed  CAS  Google Scholar 

  • Cui JH, Park K, Park SR, Min BH (2006) Effects of low-intensity ultrasound on chondrogenic differentiation of mesenchymal stem cells embedded in polyglycolic acid: an in vivo study. Tissue Eng 12:75–82

    Article  PubMed  CAS  Google Scholar 

  • Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR, Gebre-Medhin S, Galson DL, Zajac JD, Karsenty G (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol 164:509–514

    Article  PubMed  CAS  Google Scholar 

  • Darby I, Skalli O, Gabbiani G (1990) Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest 63:21–29

    PubMed  CAS  Google Scholar 

  • Daub K, Langer H, Seizer P, Stellos K, May AE, Goyal P, Bigalke B, Schonberger T, Geisler T, Siegel-Axel D, Oostendorp RA, Lindemann S, Gawaz M (2006) Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells. FASEB J 20:2559–2561

    Article  PubMed  CAS  Google Scholar 

  • Davey RA, MacLean HE, McManus JF, Findlay DM, Zajac JD (2004) Genetically modified animal models as tools for studying bone and mineral metabolism. J Bone Miner Res 19:882–892

    Article  PubMed  Google Scholar 

  • Davey RA, Turner AG, McManus JF, Chiu WS, Tjahyono F, Moore AJ, Atkins GJ, Anderson PH, Ma C, Glatt V, MacLean HE, Vincent C, Bouxsein M, Morris HA, Findlay DM, Zajac JD (2008) Calcitonin receptor plays a physiological role to protect against hypercalcemia in mice. J Bone Miner Res 23:1182–1193

    Article  PubMed  CAS  Google Scholar 

  • Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28:875–884

    Article  PubMed  CAS  Google Scholar 

  • Desmouliere A, Redard M, Darby I, Gabbiani G (1995) Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 146:56–66

    PubMed  CAS  Google Scholar 

  • Evdokiou A, Raggatt LJ, Atkins GJ, Findlay DM (1999) Calcitonin receptor-mediated growth suppression of HEK-293 cells is accompanied by induction of p21WAF1/CIP1 and G2/M arrest. Mol Endocrinol 13:1738–1750

    Article  PubMed  CAS  Google Scholar 

  • Evdokiou A, Raggatt LJ, Sakai T, Findlay DM (2000) Identification of a novel calcitonin-response element in the promoter of the human p21WAF1/CIP1 gene. J Mol Endocrinol 25:195–206

    Article  PubMed  CAS  Google Scholar 

  • Evdokiou A, Labrinidis A, Bouralexis S, Hay S, Findlay DM (2003) Induction of cell death of human osteogenic sarcoma cells by zoledronic acid resembles anoikis. Bone 33:216–228

    Article  PubMed  CAS  Google Scholar 

  • Fomchenko EI, Holland EC (2005) Stem cells and brain cancer. Exp Cell Res 306:323–329

    Article  PubMed  CAS  Google Scholar 

  • Fukada S, Uezumi A, Ikemoto M, Masuda S, Segawa M, Tanimura N, Yamamoto H, Miyagoe-Suzuki Y, Takeda S (2007) Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25:2448–2459

    Article  PubMed  CAS  Google Scholar 

  • Gronthos S, Zannettino AC, Hay SJ, Shi S, Graves SE, Kortesidis A, Simmons PJ (2003) Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J Cell Sci 116:1827–1835

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q (2004) Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 113:1258–1265

    PubMed  CAS  Google Scholar 

  • Jagger C, Gallagher A, Chambers T, Pondel M (1999) The porcine calcitonin receptor promoter directs expression of a linked reporter gene in a tissue and developmental specific manner in transgenic mice. Endocrinology 140:492–499

    Article  PubMed  CAS  Google Scholar 

  • Jagger C, Chambers T, Pondel M (2000) Transgenic mice reveal novel sites of calcitonin receptor gene expression during development. Biochem Biophys Res Commun 274:124–129

    Article  PubMed  CAS  Google Scholar 

  • Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49

    Article  PubMed  CAS  Google Scholar 

  • Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  PubMed  CAS  Google Scholar 

  • Lee SK, Goldring SR, Lorenzo JA (1995) Expression of the calcitonin receptor in bone marrow cell cultures and in bone: a specific marker of the differentiated osteoclast that is regulated by calcitonin. Endocrinology 136:4572–4581

    Article  PubMed  CAS  Google Scholar 

  • Lin HY, Harris TL, Flannery MR, Arrufo A, Kaji EH, Gorn A, Kolakowski JLF, Lodish HF, Goldring SR (1991) Expression cloning and characterization of a porcine renal calcitonin receptor. Science 254:1022–1024

    Article  PubMed  CAS  Google Scholar 

  • Moore EE, Kuestner RE, Stroop SD, Grant FJ, Matthewes SL, Brady CL, Sexton PM, Findlay DM (1995) Functionally different isoforms of the human calcitonin receptor result from alternative splicing of the gene transcript. Mol Endocrinol 9:959–968

    Article  PubMed  CAS  Google Scholar 

  • Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S (2005) Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 304:81–90

    Article  PubMed  CAS  Google Scholar 

  • Mould R, Pondel MD (2003) Calcitonin receptor gene expression in K562 chronic myelogenous leukemic cells. Cancer Cell Int 3:6

    Article  PubMed  Google Scholar 

  • Nicholson GC, Moseley JM, Sexton PM, Mendelsohn FA, Martin TJ (1986) Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization. J Clin Invest 78:355–360

    Article  PubMed  CAS  Google Scholar 

  • Nygaard S, Kuestner R, Moore E, Stroop S (1997) Phosphorylation of the human calcitonin receptor by multiple kinases is localized to the C-terminus. J Bone Miner Research 12:1681–1690

    Article  CAS  Google Scholar 

  • Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95:952–958

    PubMed  CAS  Google Scholar 

  • Phinney DG, Isakova I (2005) Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system. Curr Pharm Des 11:1255–1265

    Article  PubMed  CAS  Google Scholar 

  • Quinn J, Morfis M, Lam M, Elliott J, Kartsogiannis V, Williams E, Gillespie M, Martin T, Sexton P (1999) Calcitonin receptor antibodies in the identification of osteoclasts. Bone 25:1–8

    Article  PubMed  CAS  Google Scholar 

  • Ross R, Glomset JA (1973) Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180:1332–1339

    Article  PubMed  CAS  Google Scholar 

  • Ruengsakulrach P, Sinclair R, Komeda M, Raman J, Gordon I, Buxton B (1999) Comparative histopathology of radial artery versus internal thoracic artery and risk factors for development of intimal hyperplasia and atherosclerosis. Circulation 100:II139–II144

    PubMed  CAS  Google Scholar 

  • Sakai D, Mochida J, Iwashina T, Watanabe T, Nakai T, Ando K, Hotta T (2005) Differentiation of mesenchymal stem cells transplanted to a rabbit degenerative disc model: potential and limitations for stem cell therapy in disc regeneration. Spine 30:2379–2387

    Article  PubMed  Google Scholar 

  • Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109:1291–1302

    PubMed  CAS  Google Scholar 

  • Segre GV, Goldring SR (1993) Receptors for secretin, calcitonin, parathyroid hormone (PTH)/PTH-related peptide, vasoactive intestinal peptide, glucagonlike peptide 1, growth hormone-releasing hormone, and glucagon belong to a newly discovered G-protein-linked receptor family. Trends Endocrinol Metab 4:309–314

    Article  PubMed  CAS  Google Scholar 

  • Serafini M, Dylla SJ, Oki M, Heremans Y, Tolar J, Jiang Y, Buckley SM, Pelacho B, Burns TC, Frommer S, Rossi DJ, Bryder D, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Nelson-Holte M, Fine GC, Weissman IL, Blazar BR, Verfaillie CM (2007) Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. J Exp Med 204:129–139

    Article  PubMed  CAS  Google Scholar 

  • Shirley D, Marsh D, Jordan G, McQuaid S, Li G (2005) Systemic recruitment of osteoblastic cells in fracture healing. J Orthop Res 23:1013–1021

    Article  PubMed  Google Scholar 

  • Shyu J, Inoue D, Baron R, Horne W (1996) The deletion of 14 amino acids in the seventh transmembrane domain of a naturally occurring calcitonin receptor isoform alters ligand binding and selectively abolishes coupling to phospholipase C. J Biol Chem 271:31127–31134

    Article  PubMed  CAS  Google Scholar 

  • Silvestris F, Cafforio P, De Matteo M, Quatraro C, Dammacco F (2008) Expression and function of the calcitonin receptor by myeloma cells in their osteoclast-like activity in vitro. Leuk Res 32:611–623

    Article  PubMed  CAS  Google Scholar 

  • Simmons RE, Hjelle JT, Mahoney C, Deftos LJ, Lisker W, Kato P, Rabkin R (1988) Renal metabolism of calcitonin. Am J Physiol 254:F593–F600

    PubMed  CAS  Google Scholar 

  • Tikellis C, Xuereb L, Casley D, Brasier G, Cooper ME, Wookey PJ (2003) Calcitonin receptor isoforms expressed in the developing rat kidney. Kidney Int 63:416–426

    Article  PubMed  CAS  Google Scholar 

  • Tolar J, Osborn M, Bell S, McElmurry R, Xia L, Riddle M, Panoskaltsis-Mortari A, Jiang Y, McIvor RS, Contag CH, Yant SR, Kay MA, Verfaillie CM, Blazar BR (2005) Real-time in vivo imaging of stem cells following transgenesis by transposition. Mol Ther 12:42–48

    Article  PubMed  CAS  Google Scholar 

  • Tolcos M, Tikellis C, Rees S, Cooper M, Wookey P (2003) Ontogeny of calcitonin receptor mRNA and protein in the developing central nervous system of the rat. J Comp Neurol 456:29–38

    Article  PubMed  CAS  Google Scholar 

  • Wookey P, Zulli A, Buxton B, Hare D (2008) Calcitonin receptor immunoreactivity associated with specific cell types in diseased radial and internal mammary arteries. Histopathology 52:605–612

    Article  PubMed  CAS  Google Scholar 

  • Wookey P, Zulli A, Lo C, Hare D, Schwarer A, Darby I, Leung A (2009) Calcitonin receptor (CTR) expression in embryonic, foetal and adult tissues: developmental and pathophysiological implications. In: Hay D, Dickerson I (eds) The calcitonin gene-related peptide family; form, function and future perspectives. Springer, Dordrecht (in press)

  • Wu X, Huang L, Zhou Q, Song Y, Li A, Wang H, Song M (2005) Effect of paclitaxel and mesenchymal stem cells seeding on ex vivo vascular endothelial repair and smooth muscle cells growth. J Cardiovasc Pharmacol 46:779–786

    Article  PubMed  CAS  Google Scholar 

  • Xu Q, Zhang Z, Davison F, Hu Y (2003) Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice. Circ Res 93:e76–e86

    Article  PubMed  CAS  Google Scholar 

  • Yoo SD, Jun H, Shin BS, Lee HS, Park MO, Deluca PP, Lee KC (2000) Pharmacokinetic disposition of polyethylene glycol-modified salmon calcitonins in rats. Chem Pharm Bull (Tokyo) 48:1921–1924

    CAS  Google Scholar 

  • Zaidi M, Pazianas M, Shankar VS, Bax BE, Bax CM, Bevis PJ, Stevens C, Huang CL, Blake DR, Moonga BS et al (1993) Osteoclast function and its control. Exp Physiol 78:721–739

    PubMed  CAS  Google Scholar 

  • Zulli A, Widdop RE, Hare DL, Buxton BF, Black MJ (2003) High methionine and cholesterol diet abolishes endothelial relaxation. Arterioscler Thromb Vasc Biol 23:1358–1363

    Article  PubMed  CAS  Google Scholar 

  • Zulli A, Buxton BF, Black MJ, Hare DL (2005) CD34 Class III positive cells are present in atherosclerotic plaques of the rabbit model of atherosclerosis. Histochem Cell Biol 124:517–522

    Article  PubMed  CAS  Google Scholar 

  • Zulli A, Buxton BF, Black MJ, Ming Z, Cameron A, Hare DL (2006) The immunoquantification of caveolin-1 and eNOS in human and rabbit diseased blood vessels. J Histochem Cytochem 54:151–159

    Article  PubMed  CAS  Google Scholar 

  • Zulli A, Buxton BF, Black MJ, Hare DL (2008) Embryonic stem cell markers are present within rabbit atherosclerotic plaques. Histol Histopathol 23:741–746

    PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Health and Medical Research Council, National Heart Foundation of Australia and the Austin Hospital Medical Research Foundation.

Author information

Authors and Affiliations

  1. Departments of Cardiology and Medicine, University of Melbourne, Austin Health, Austin Campus, Studley Road, Heidelberg, VIC, 3084, Australia

    Peter J. Wookey, Anthony Zulli & David L. Hare

Authors
  1. Peter J. Wookey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony Zulli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. Hare
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Wookey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wookey, P.J., Zulli, A. & Hare, D.L. The elevated expression of calcitonin receptor by cells recruited into the endothelial layer and neo-intima of atherosclerotic plaque. Histochem Cell Biol 132, 181–189 (2009). https://doi.org/10.1007/s00418-009-0600-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-009-0600-6

Keywords

Search

Navigation