Abstract
Expansion of atherosclerotic abdominal aortic aneurysm (AAA) has been attributed to remodeling of the extracellular matrix by active proteolysis. We used in situ hybridization to analyze the expression of fibrinolytic genes in aneurysm wall from eight AAA patients. All specimens exhibited specific areas of inflammatory infiltrates with macrophage-like cells expressing urokinase-type plasminogen activator (u-PA) and tissue-type PA (t-PA) mRNA. Type 1 PA inhibitor (PAI-1) mRNA was expressed at the base of the necrotic atheroma of all specimens and also within some of the inflammatory infiltrates where it frequently colocalized in regions containing u-PA and t-PA mRNA expressing cells. However, in these areas, the cellular distribution of the transcripts for t-PA and u-PA extended far beyond the areas of PAI-1 expression. These observations suggest a local ongoing proteolytic process, one which is only partially counteracted by the more restricted expression of PAI-1 mRNA. An abundance of capillaries was also obvious in all inflammatory infiltrates and may reflect local angiogenesis in response to active pericellular fibrinolysis. The increased fibrinolytic capacity in AAA wall may promote angiogenesis and contribute to local proteolytic degradation of the aortic wall leading to physical weakening and active expansion of the aneurysm.
Full text
PDF






Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- ASTRUP T., COCCHERI S. Thromboplastic and fibrinolytic activity of the arteriosclerotic human aorta. Nature. 1962 Jan 13;193:182–183. doi: 10.1038/193182a0. [DOI] [PubMed] [Google Scholar]
- Alpern-Elran H., Morog N., Robert F., Hoover G., Kalant N., Brem S. Angiogenic activity of the atherosclerotic carotid artery plaque. J Neurosurg. 1989 Jun;70(6):942–945. doi: 10.3171/jns.1989.70.6.0942. [DOI] [PubMed] [Google Scholar]
- Anidjar S., Dobrin P. B., Eichorst M., Graham G. P., Chejfec G. Correlation of inflammatory infiltrate with the enlargement of experimental aortic aneurysms. J Vasc Surg. 1992 Aug;16(2):139–147. doi: 10.1067/mva.1992.35585. [DOI] [PubMed] [Google Scholar]
- Anidjar S., Salzmann J. L., Gentric D., Lagneau P., Camilleri J. P., Michel J. B. Elastase-induced experimental aneurysms in rats. Circulation. 1990 Sep;82(3):973–981. doi: 10.1161/01.cir.82.3.973. [DOI] [PubMed] [Google Scholar]
- Bacharach E., Itin A., Keshet E. In vivo patterns of expression of urokinase and its inhibitor PAI-1 suggest a concerted role in regulating physiological angiogenesis. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10686–10690. doi: 10.1073/pnas.89.22.10686. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barath P., Fishbein M. C., Cao J., Berenson J., Helfant R. H., Forrester J. S. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990 Feb 1;65(5):297–302. doi: 10.1016/0002-9149(90)90291-8. [DOI] [PubMed] [Google Scholar]
- Barger A. C., Beeuwkes R., 3rd, Lainey L. L., Silverman K. J. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med. 1984 Jan 19;310(3):175–177. doi: 10.1056/NEJM198401193100307. [DOI] [PubMed] [Google Scholar]
- Busuttil R. W., Abou-Zamzam A. M., Machleder H. I. Collagenase activity of the human aorta. A comparison of patients with and without abdominal aortic aneurysms. Arch Surg. 1980 Nov;115(11):1373–1378. doi: 10.1001/archsurg.1980.01380110105016. [DOI] [PubMed] [Google Scholar]
- Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
- Declerck P. J., De Mol M., Alessi M. C., Baudner S., Pâques E. P., Preissner K. T., Müller-Berghaus G., Collen D. Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin). J Biol Chem. 1988 Oct 25;263(30):15454–15461. [PubMed] [Google Scholar]
- Folkman J., Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. doi: 10.1126/science.2432664. [DOI] [PubMed] [Google Scholar]
- GEIRINGER E. Intimal vascularization and atherosclerosis. J Pathol Bacteriol. 1951 Apr;63(2):201–211. doi: 10.1002/path.1700630204. [DOI] [PubMed] [Google Scholar]
- 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]
- Guettier C., Hinglais N., Bruneval P., Kazatchkine M., Bariety J., Camilleri J. P. Immunohistochemical localization of S protein/vitronectin in human atherosclerotic versus arteriosclerotic arteries. Virchows Arch A Pathol Anat Histopathol. 1989;414(4):309–313. doi: 10.1007/BF00734084. [DOI] [PubMed] [Google Scholar]
- Hughes S. E., Crossman D., Hall P. A. Expression of basic and acidic fibroblast growth factors and their receptor in normal and atherosclerotic human arteries. Cardiovasc Res. 1993 Jul;27(7):1214–1219. doi: 10.1093/cvr/27.7.1214. [DOI] [PubMed] [Google Scholar]
- Jean-Claude J., Newman K. M., Li H., Gregory A. K., Tilson M. D. Possible key role for plasmin in the pathogenesis of abdominal aortic aneurysms. Surgery. 1994 Aug;116(2):472–478. [PubMed] [Google Scholar]
- Kamat B. R., Galli S. J., Barger A. C., Lainey L. L., Silverman K. J. Neovascularization and coronary atherosclerotic plaque: cinematographic localization and quantitative histologic analysis. Hum Pathol. 1987 Oct;18(10):1036–1042. doi: 10.1016/s0046-8177(87)80220-4. [DOI] [PubMed] [Google Scholar]
- Keeton M., Eguchi Y., Sawdey M., Ahn C., Loskutoff D. J. Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue. Am J Pathol. 1993 Jan;142(1):59–70. [PMC free article] [PubMed] [Google Scholar]
- Koch A. E., Haines G. K., Rizzo R. J., Radosevich J. A., Pope R. M., Robinson P. G., Pearce W. H. Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol. 1990 Nov;137(5):1199–1213. [PMC free article] [PubMed] [Google Scholar]
- Lendon C. L., Davies M. J., Born G. V., Richardson P. D. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis. 1991 Mar;87(1):87–90. doi: 10.1016/0021-9150(91)90235-u. [DOI] [PubMed] [Google Scholar]
- Liotta L. A., Rao C. N., Wewer U. M. Biochemical interactions of tumor cells with the basement membrane. Annu Rev Biochem. 1986;55:1037–1057. doi: 10.1146/annurev.bi.55.070186.005133. [DOI] [PubMed] [Google Scholar]
- Lupu F., Bergonzelli G. E., Heim D. A., Cousin E., Genton C. Y., Bachmann F., Kruithof E. K. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb. 1993 Jul;13(7):1090–1100. doi: 10.1161/01.atv.13.7.1090. [DOI] [PubMed] [Google Scholar]
- Lusby R. J., Ferrell L. D., Ehrenfeld W. K., Stoney R. J., Wylie E. J. Carotid plaque hemorrhage. Its role in production of cerebral ischemia. Arch Surg. 1982 Nov;117(11):1479–1488. doi: 10.1001/archsurg.1982.01380350069010. [DOI] [PubMed] [Google Scholar]
- Miettinen M., Lindenmayer A. E., Chaubal A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens--evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol. 1994 Jan;7(1):82–90. [PubMed] [Google Scholar]
- Mimuro J., Loskutoff D. J. Purification of a protein from bovine plasma that binds to type 1 plasminogen activator inhibitor and prevents its interaction with extracellular matrix. Evidence that the protein is vitronectin. J Biol Chem. 1989 Jan 15;264(2):936–939. [PubMed] [Google Scholar]
- Moscatelli D., Rifkin D. B. Membrane and matrix localization of proteinases: a common theme in tumor cell invasion and angiogenesis. Biochim Biophys Acta. 1988 Aug 3;948(1):67–85. doi: 10.1016/0304-419x(88)90005-4. [DOI] [PubMed] [Google Scholar]
- Munro J. M., Cotran R. S. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest. 1988 Mar;58(3):249–261. [PubMed] [Google Scholar]
- Murphy G., Atkinson S., Ward R., Gavrilovic J., Reynolds J. J. The role of plasminogen activators in the regulation of connective tissue metalloproteinases. Ann N Y Acad Sci. 1992 Dec 4;667:1–12. doi: 10.1111/j.1749-6632.1992.tb51590.x. [DOI] [PubMed] [Google Scholar]
- Nathan C. F. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. doi: 10.1172/JCI112815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Newman K. M., Ogata Y., Malon A. M., Irizarry E., Gandhi R. H., Nagase H., Tilson M. D. Identification of matrix metalloproteinases 3 (stromelysin-1) and 9 (gelatinase B) in abdominal aortic aneurysm. Arterioscler Thromb. 1994 Aug;14(8):1315–1320. doi: 10.1161/01.atv.14.8.1315. [DOI] [PubMed] [Google Scholar]
- Niculescu F., Rus H. G., Poruţiu D., Ghiurca V., Vlaicu R. Immunoelectron-microscopic localization of S-protein/vitronectin in human atherosclerotic wall. Atherosclerosis. 1989 Aug;78(2-3):197–203. doi: 10.1016/0021-9150(89)90223-2. [DOI] [PubMed] [Google Scholar]
- Ny T., Elgh F., Lund B. The structure of the human tissue-type plasminogen activator gene: correlation of intron and exon structures to functional and structural domains. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5355–5359. doi: 10.1073/pnas.81.17.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ny T., Sawdey M., Lawrence D., Millan J. L., Loskutoff D. J. Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6776–6780. doi: 10.1073/pnas.83.18.6776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Powell J., Greenhalgh R. M. Cellular, enzymatic, and genetic factors in the pathogenesis of abdominal aortic aneurysms. J Vasc Surg. 1989 Feb;9(2):297–304. doi: 10.1067/mva.1989.vs0090297. [DOI] [PubMed] [Google Scholar]
- Reilly J. M., Sicard G. A., Lucore C. L. Abnormal expression of plasminogen activators in aortic aneurysmal and occlusive disease. J Vasc Surg. 1994 May;19(5):865–872. doi: 10.1016/s0741-5214(94)70012-5. [DOI] [PubMed] [Google Scholar]
- Rijken D. C., Wijngaards G., Welbergen J. Relationship between tissue plasminogen activator and the activators in blood and vascular wall. Thromb Res. 1980 Jun 15;18(6):815–830. doi: 10.1016/0049-3848(80)90204-2. [DOI] [PubMed] [Google Scholar]
- Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
- Schneiderman J., Sawdey M. S., Keeton M. R., Bordin G. M., Bernstein E. F., Dilley R. B., Loskutoff D. J. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6998–7002. doi: 10.1073/pnas.89.15.6998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sueishi K., Yasunaga C., Castellanos E., Kumamoto M., Tanaka K. Sustained arterial injury and progression of atherosclerosis. Ann N Y Acad Sci. 1990;598:223–231. doi: 10.1111/j.1749-6632.1990.tb42294.x. [DOI] [PubMed] [Google Scholar]
- Tipping P. G., Hancock W. W. Production of tumor necrosis factor and interleukin-1 by macrophages from human atheromatous plaques. Am J Pathol. 1993 Jun;142(6):1721–1728. [PMC free article] [PubMed] [Google Scholar]
- Tromholt N., Jørgensen S. J., Hesse B., Hansen M. S. In vivo demonstration of focal fibrinolytic activity in abdominal aortic aneurysms. Eur J Vasc Surg. 1993 Nov;7(6):675–679. doi: 10.1016/s0950-821x(05)80715-7. [DOI] [PubMed] [Google Scholar]
- Wolinsky H., Glagov S. Comparison of abdominal and thoracic aortic medial structure in mammals. Deviation of man from the usual pattern. Circ Res. 1969 Dec;25(6):677–686. doi: 10.1161/01.res.25.6.677. [DOI] [PubMed] [Google Scholar]
- Zarins C. K., Runyon-Hass A., Zatina M. A., Lu C. T., Glagov S. Increased collagenase activity in early aneurysmal dilatation. J Vasc Surg. 1986 Feb;3(2):238–248. doi: 10.1067/mva.1986.avs0030238. [DOI] [PubMed] [Google Scholar]
- van der Wal A. C., Becker A. E., van der Loos C. M., Das P. K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994 Jan;89(1):36–44. doi: 10.1161/01.cir.89.1.36. [DOI] [PubMed] [Google Scholar]