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. 1993 Feb;142(2):593–606.

Gap junctional communication between vascular cells. Induction of connexin43 messenger RNA in macrophage foam cells of atherosclerotic lesions.

D Polacek 1, R Lal 1, M V Volin 1, P F Davies 1
PMCID: PMC1886737  PMID: 8382009

Abstract

The structure and function of blood vessels depend on the ability of vascular cells to receive and transduce signals and to communicate with each other. One means by which vascular cells have been shown to communicate is via gap junctions, specifically connexin43. In atherosclerosis, the normal physical patterns of communication are disrupted by the subendothelial infiltration and accumulation of blood monocytes, which in turn can differentiate into resident foam cells. In this paper we report that neither freshly isolated human peripheral blood monocytes nor differentiated monocytes/macrophages exhibit functional gap junctional dye transfer in homo-cellular culture or in co-culture with endothelial cells or smooth muscle cells. By Northern analysis, neither freshly isolated blood monocytes nor pure cultures of differentiated monocyte/macrophages expressed gap junction messenger RNA. However, immunohistochemical staining followed by in situ hybridization on sections of human atherosclerotic carotid arteries revealed strong expression of gap junction connexin43 messenger RNA by macrophage foam cells. These results suggest that tissue-specific conditions present in atherosclerotic arteries induce expression of connexin43 messenger RNA in monocyte/macrophages.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berliner J. A., Territo M. C., Sevanian A., Ramin S., Kim J. A., Bamshad B., Esterson M., Fogelman A. M. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990 Apr;85(4):1260–1266. doi: 10.1172/JCI114562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beyer E. C., Paul D. L., Goodenough D. A. Connexin family of gap junction proteins. J Membr Biol. 1990 Jul;116(3):187–194. doi: 10.1007/BF01868459. [DOI] [PubMed] [Google Scholar]
  3. Beyer E. C., Paul D. L., Goodenough D. A. Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J Cell Biol. 1987 Dec;105(6 Pt 1):2621–2629. doi: 10.1083/jcb.105.6.2621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beyer E. C., Steinberg T. H. Evidence that the gap junction protein connexin-43 is the ATP-induced pore of mouse macrophages. J Biol Chem. 1991 May 5;266(13):7971–7974. [PubMed] [Google Scholar]
  5. Bény J. L., Connat J. L. An electron-microscopic study of smooth muscle cell dye coupling in the pig coronary arteries. Role of gap junctions. Circ Res. 1992 Jan;70(1):49–55. doi: 10.1161/01.res.70.1.49. [DOI] [PubMed] [Google Scholar]
  6. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  7. Cushing S. D., Berliner J. A., Valente A. J., Territo M. C., Navab M., Parhami F., Gerrity R., Schwartz C. J., Fogelman A. M. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5134–5138. doi: 10.1073/pnas.87.13.5134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cybulsky M. I., Gimbrone M. A., Jr Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991 Feb 15;251(4995):788–791. doi: 10.1126/science.1990440. [DOI] [PubMed] [Google Scholar]
  9. Davies P. F., Ganz P., Diehl P. S. Reversible microcarrier-mediated junctional communication between endothelial and smooth muscle cell monolayers: an in vitro model of vascular cell interactions. Lab Invest. 1985 Dec;53(6):710–718. [PubMed] [Google Scholar]
  10. Davies P. F., Olesen S. P., Clapham D. E., Morrel E. M., Schoen F. J. Endothelial communication. State of the art lecture. Hypertension. 1988 Jun;11(6 Pt 2):563–572. doi: 10.1161/01.hyp.11.6.563.a. [DOI] [PubMed] [Google Scholar]
  11. Davies P. F., Truskey G. A., Warren H. B., O'Connor S. E., Eisenhaure B. H. Metabolic cooperation between vascular endothelial cells and smooth muscle cells in co-culture: changes in low density lipoprotein metabolism. J Cell Biol. 1985 Sep;101(3):871–879. doi: 10.1083/jcb.101.3.871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fogelman A. M., Elahi F., Sykes K., Van Lenten B. J., Territo M. C., Berliner J. A. Modification of the Recalde method for the isolation of human monocytes. J Lipid Res. 1988 Sep;29(9):1243–1247. [PubMed] [Google Scholar]
  13. Gordon D., Reidy M. A., Benditt E. P., Schwartz S. M. Cell proliferation in human coronary arteries. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4600–4604. doi: 10.1073/pnas.87.12.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gown A. M., Tsukada T., Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986 Oct;125(1):191–207. [PMC free article] [PubMed] [Google Scholar]
  15. Guthrie S. C., Gilula N. B. Gap junctional communication and development. Trends Neurosci. 1989 Jan;12(1):12–16. doi: 10.1016/0166-2236(89)90150-1. [DOI] [PubMed] [Google Scholar]
  16. Hoh J. H., John S. A., Revel J. P. Molecular cloning and characterization of a new member of the gap junction gene family, connexin-31. J Biol Chem. 1991 Apr 5;266(10):6524–6531. [PubMed] [Google Scholar]
  17. Hüttner I., Peters H. Heterogeneity of cell junctions in rat aortic endothelium: a freeze-fracture study. J Ultrastruct Res. 1978 Sep;64(3):303–308. doi: 10.1016/s0022-5320(78)90038-2. [DOI] [PubMed] [Google Scholar]
  18. Jongen W. M., Fitzgerald D. J., Asamoto M., Piccoli C., Slaga T. J., Gros D., Takeichi M., Yamasaki H. Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin. J Cell Biol. 1991 Aug;114(3):545–555. doi: 10.1083/jcb.114.3.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kalimi G. H., Sirsat S. M. Phorbol ester tumor promoter affects the mouse epidermal gap junctions. Cancer Lett. 1984 Apr;22(3):343–350. doi: 10.1016/0304-3835(84)90173-3. [DOI] [PubMed] [Google Scholar]
  20. Kanter H. L., Saffitz J. E., Beyer E. C. Cardiac myocytes express multiple gap junction proteins. Circ Res. 1992 Feb;70(2):438–444. doi: 10.1161/01.res.70.2.438. [DOI] [PubMed] [Google Scholar]
  21. Keane R. W., Mehta P. P., Rose B., Honig L. S., Loewenstein W. R., Rutishauser U. Neural differentiation, NCAM-mediated adhesion, and gap junctional communication in neuroectoderm. A study in vitro. J Cell Biol. 1988 Apr;106(4):1307–1319. doi: 10.1083/jcb.106.4.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Larson D. M., Haudenschild C. C., Beyer E. C. Gap junction messenger RNA expression by vascular wall cells. Circ Res. 1990 Apr;66(4):1074–1080. doi: 10.1161/01.res.66.4.1074. [DOI] [PubMed] [Google Scholar]
  23. Larson D. M., Haudenschild C. C. Junctional transfer in wounded cultures of bovine aortic endothelial cells. Lab Invest. 1988 Sep;59(3):373–379. [PubMed] [Google Scholar]
  24. Larson D. M., Sheridan J. D. Intercellular junctions and transfer of small molecules in primary vascular endothelial cultures. J Cell Biol. 1982 Jan;92(1):183–191. doi: 10.1083/jcb.92.1.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Larson D. M., Sheridan J. D. Junctional transfer in cultured vascular endothelium: II. Dye and nucleotide transfer. J Membr Biol. 1985;83(1-2):157–167. doi: 10.1007/BF01868747. [DOI] [PubMed] [Google Scholar]
  26. Loewenstein W. R. The cell-to-cell channel of gap junctions. Cell. 1987 Mar 13;48(5):725–726. doi: 10.1016/0092-8674(87)90067-5. [DOI] [PubMed] [Google Scholar]
  27. Maldonado P. E., Rose B., Loewenstein W. R. Growth factors modulate junctional cell-to-cell communication. J Membr Biol. 1988 Dec;106(3):203–210. doi: 10.1007/BF01872158. [DOI] [PubMed] [Google Scholar]
  28. Meda P., Chanson M., Pepper M., Giordano E., Bosco D., Traub O., Willecke K., el Aoumari A., Gros D., Beyer E. C. In vivo modulation of connexin 43 gene expression and junctional coupling of pancreatic B-cells. Exp Cell Res. 1991 Feb;192(2):469–480. doi: 10.1016/0014-4827(91)90066-4. [DOI] [PubMed] [Google Scholar]
  29. Mege R. M., Matsuzaki F., Gallin W. J., Goldberg J. I., Cunningham B. A., Edelman G. M. Construction of epithelioid sheets by transfection of mouse sarcoma cells with cDNAs for chicken cell adhesion molecules. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7274–7278. doi: 10.1073/pnas.85.19.7274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mehta P. P., Bertram J. S., Loewenstein W. R. The actions of retinoids on cellular growth correlate with their actions on gap junctional communication. J Cell Biol. 1989 Mar;108(3):1053–1065. doi: 10.1083/jcb.108.3.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Milks L. C., Kumar N. M., Houghten R., Unwin N., Gilula N. B. Topology of the 32-kd liver gap junction protein determined by site-directed antibody localizations. EMBO J. 1988 Oct;7(10):2967–2975. doi: 10.1002/j.1460-2075.1988.tb03159.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Navab M., Liao F., Hough G. P., Ross L. A., Van Lenten B. J., Rajavashisth T. B., Lusis A. J., Laks H., Drinkwater D. C., Fogelman A. M. Interaction of monocytes with cocultures of human aortic wall cells involves interleukins 1 and 6 with marked increases in connexin43 message. J Clin Invest. 1991 May;87(5):1763–1772. doi: 10.1172/JCI115195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nelken N. A., Coughlin S. R., Gordon D., Wilcox J. N. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991 Oct;88(4):1121–1127. doi: 10.1172/JCI115411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Paul D. L. Molecular cloning of cDNA for rat liver gap junction protein. J Cell Biol. 1986 Jul;103(1):123–134. doi: 10.1083/jcb.103.1.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pawlowski N. A., Abraham E. L., Pontier S., Scott W. A., Cohn Z. A. Human monocyte-endothelial cell interaction in vitro. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8208–8212. doi: 10.1073/pnas.82.23.8208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pritchard K. A., Jr, Tota R. R., Lin J. H., Danishefsky K. J., Kurilla B. A., Holland J. A., Stemerman M. B. Native low density lipoprotein. Endothelial cell recruitment of mononuclear cells. Arterioscler Thromb. 1991 Sep-Oct;11(5):1175–1181. doi: 10.1161/01.atv.11.5.1175. [DOI] [PubMed] [Google Scholar]
  37. Revel J. P., Karnovsky M. J. Hexagonal array of subunits in intercellular junctions of the mouse heart and liver. J Cell Biol. 1967 Jun;33(3):C7–C12. doi: 10.1083/jcb.33.3.c7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rhodin J. A. The ultrastructure of mammalian arterioles and precapillary sphincters. J Ultrastruct Res. 1967 Apr;18(1):181–223. doi: 10.1016/s0022-5320(67)80239-9. [DOI] [PubMed] [Google Scholar]
  39. Rhodin J. A. Ultrastructure of mammalian venous capillaries, venules, and small collecting veins. J Ultrastruct Res. 1968 Dec;25(5):452–500. doi: 10.1016/s0022-5320(68)80098-x. [DOI] [PubMed] [Google Scholar]
  40. Rice G. E., Munro J. M., Corless C., Bevilacqua M. P. Vascular and nonvascular expression of INCAM-110. A target for mononuclear leukocyte adhesion in normal and inflamed human tissues. Am J Pathol. 1991 Feb;138(2):385–393. [PMC free article] [PubMed] [Google Scholar]
  41. Rosenfeld M. E., Ross R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 1990 Sep-Oct;10(5):680–687. doi: 10.1161/01.atv.10.5.680. [DOI] [PubMed] [Google Scholar]
  42. Rosenfeld M. E., Ylä-Herttuala S., Lipton B. A., Ord V. A., Witztum J. L., Steinberg D. Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans. Am J Pathol. 1992 Feb;140(2):291–300. [PMC free article] [PubMed] [Google Scholar]
  43. Ross R., Masuda J., Raines E. W., Gown A. M., Katsuda S., Sasahara M., Malden L. T., Masuko H., Sato H. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science. 1990 May 25;248(4958):1009–1012. doi: 10.1126/science.2343305. [DOI] [PubMed] [Google Scholar]
  44. Rutten A. A., Jongen W. M., de Haan L. H., Hendriksen E. G., Koeman J. H. Effect of retinol and cigarette-smoke condensate on dye-coupled intercellular communication between hamster tracheal epithelial cells. Carcinogenesis. 1988 Feb;9(2):315–320. doi: 10.1093/carcin/9.2.315. [DOI] [PubMed] [Google Scholar]
  45. Swenson K. I., Piwnica-Worms H., McNamee H., Paul D. L. Tyrosine phosphorylation of the gap junction protein connexin43 is required for the pp60v-src-induced inhibition of communication. Cell Regul. 1990 Dec;1(13):989–1002. doi: 10.1091/mbc.1.13.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tsukada T., Tippens D., Gordon D., Ross R., Gown A. M. HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization. Am J Pathol. 1987 Jan;126(1):51–60. [PMC free article] [PubMed] [Google Scholar]
  47. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Yancey S. B., Edens J. E., Trosko J. E., Chang C. C., Revel J. P. Decreased incidence of gap junctions between Chinese hamster V-79 cells upon exposure to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate. Exp Cell Res. 1982 Jun;139(2):329–340. doi: 10.1016/0014-4827(82)90257-9. [DOI] [PubMed] [Google Scholar]
  49. Yancey S. B., John S. A., Lal R., Austin B. J., Revel J. P. The 43-kD polypeptide of heart gap junctions: immunolocalization, topology, and functional domains. J Cell Biol. 1989 Jun;108(6):2241–2254. doi: 10.1083/jcb.108.6.2241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ylä-Herttuala S., Lipton B. A., Rosenfeld M. E., Särkioja T., Yoshimura T., Leonard E. J., Witztum J. L., Steinberg D. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5252–5256. doi: 10.1073/pnas.88.12.5252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yotti L. P., Chang C. C., Trosko J. E. Elimination of metabolic cooperation in Chinese hamster cells by a tumor promoter. Science. 1979 Nov 30;206(4422):1089–1091. doi: 10.1126/science.493994. [DOI] [PubMed] [Google Scholar]
  52. Zwijsen R. M., de Haan L. H., Oosting J. S., Pekelharing H. L., Koeman J. H. Inhibition of intercellular communication in smooth muscle cells of humans and rats by low density lipoprotein, cigarette smoke condensate and TPA. Atherosclerosis. 1990 Nov;85(1):71–80. doi: 10.1016/0021-9150(90)90184-k. [DOI] [PubMed] [Google Scholar]

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