Three reactive compartments in venous malformations
11. Januar 2007
Accepted after revision 08. März 2007
24. November 2017 (online)
Vascular malformations affect 3% of neonates. Venous malformations (VMs) are the largest group representing more than 50% of cases. In hereditary forms of VMs gene mutations have been identified, but for the large group of spontaneous forms the primary cause and downstream dysregulated genes are unknown. We have performed a global comparison of gene expression in slow-flow VMs and normal saphenous veins using human whole genome micro-arrays.Genes of interest were validated with qRT-PCR. Gene expression in the tunica media was studied after laser micro-dissection of small pieces of tissue. Protein expression in endothelial cells (ECs) was studied with antibodies.We detected 511 genes more than four-fold down- and 112 genes more than four-fold up-regulated. Notably, chemokines, growth factors, transcription factors and regulators of extra-cellular matrix (ECM) turnover were regulated. We observed activation and “arterialization” of ECs of the VM proper, whereas ECs of vasa vasorum exhibited up-regulation of inflammation markers. In the tunica media, an altered ECM turnover and composition was found. Our studies demonstrate dysregulated gene expression in tunica interna, media and externa of VMs, and show that each of the three layers represents a reactive compartment.The dysregulated genes may serve as therapeutic targets.
KeywordsVenous malformation - chemokines - growth factors - transcription factors - extracellular matrix
* These authors contributed equally.
- 1 Osburn K, Schosser RH, Everett MA. Congenital pigmented and vascular lesions in newborn infants. J Am Acad Dermatol 1987; 16: 788-792.
- 2 Boon LM, Mulliken JB, Vikkula M. et al. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet 1994; 03: 1583-1587.
- 3 Vikkula M, Boon LM, Carraway KL 3rd. et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996; 87: 1181-1190.
- 4 Mulliken JY. AE. Vascular Birthmarks: Hemangiomas and malformations. Philadelphia, PA: WB Saunders Co; 1988
- 5 van Korlaar I, Vossen C, Rosendaal F. et al. Quality of life in venous disease. Thromb Haemost 2003; 90: 27-35.
- 6 Laberge-le Couteulx S JH, Labauge P, Houtteville JP. et al. Truncating mutations in CCM1, encoding Krit1, cause hereditary cavernous angiomas. Nat Genet 1999; 23: 189-193.
- 7 Serebriiskii I, Estojak J, Sonoda G. et al. Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat- containing protein encoded by a gene mapping to 7q21–22. Oncogene 1997; 15: 1043-1049.
- 8 Brouillard P, Olsen BR, Vikkula M. High-resolution physical and transcript map of the locus for venous malformations with glomus cells (VMGLOM) on chromosome 1p21-p22. Genomics 2000; 67: 96-101.
- 9 Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev 2005; 15: 265-269.
- 10 Diehl S, Bruno R, Wilkinson GA. et al. Altered expression patterns of EphrinB2 and EphB2 in human umbilical vessels and congenital venous malformations. Pediatr Res 2005; 57: 537-544.
- 11 Bretz F, Landgrebe J, Brunner E. Multiplicity issues in microarray experiments. Methods Inf Med 2005; 44: 431-437.
- 12 Schlingemann RO, Dingjan GM, Emeis JJ. et al. Monoclonal antibody PAL-E specific for endothelium. Lab Invest 1985; 52: 71-76.
- 13 Boon LM, Mulliken JB, Enjolras O. et al. Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol 2004; 140: 971-976.
- 14 Gu L, Tseng SC, Rollins BJ. Monocyte chemoattractant protein-1. Chem Immunol 1999; 72: 7-29.
- 15 Koch AE, Kunkel SL, Harlow LA. et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 1992; 90: 772-779.
- 16 Galindo M, Santiago B, Rivero M. et al. Chemokine expression by systemic sclerosis fibroblasts: abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum 2001; 44: 1382-1386.
- 17 Distler O, Pap T, Kowal-Bielecka O. et al. Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth fac tor and effects on monocyte chemotaxis and collagen synthesis. Arthritis Rheum 2001; 44: 2665-2678.
- 18 Guo M, Sahni SK, Sahni A. et al. Fibrinogen regulates the expression of inflammatory chemokines through NF-kappaB activation of endothelial cells. Thromb Haemost 2004; 92: 858-866.
- 19 Proost P, Wuyts A, Van Damme J. Human monocyte chemotactic proteins-2 and –3: structural and functional comparison with MCP-1. J Leukoc Biol 1996; 59: 67-74.
- 20 Simmons D, Makgoba MW, Seed B. ICAM, an adhesion ligand of LFA-1, is homologous to the neural cell adhesion molecule NCAM. Nature 1988; 331: 624-627.
- 21 Pascarella L, Schonbein GW, Bergan JJ. Microcirculation and venous ulcers: a review. Ann Vasc Surg 2005; 19: 921-927.
- 22 Lebedeva T, Dustin ML, Sykulev Y. ICAM-1 costimulates target cells to facilitate antigen presentation. Curr Opin Immunol 2005; 17: 251-258.
- 23 Bevilacqua MP, Stengelin S, Gimbrone MA Jr. et al. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 1989; 243: 1160-1165.
- 24 Ferrario CM, Strawn WB. Role of the renin-angiotensin- aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 2006; 98: 121-128.
- 25 Ebert LM, Schaerli P, Moser B. Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. Mol Immunol 2005; 42: 799-809.
- 26 Ruberte J, Ayuso E, Navarro M. et al. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes- like eye disease. J Clin Invest 2004; 113: 1149-1157.
- 27 Pedone PV, Tirabosco R, Cavazzana AO. et al. Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. Hum Mol Genet 1994; 03: 1117-1121.
- 28 Wang Q, Bardgett ME, Wong M. et al. Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 2002; 35: 25-38.
- 29 Chen H, Weber AJ. BDNF enhances retinal ganglion cell survival in cats with optic nerve damage. Invest Ophthalmol Vis Sci 2001; 42: 966-974.
- 30 Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature 2005; 436: 193-200.
- 31 Dong J, Albertini DF, Nishimori K. et al. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 1996; 383: 531-535.
- 32 Badier-Commander C, Couvelard A, Henin D. et al. Smooth muscle cell modulation and cytokine overproduction in varicose veins. An in situ study. J Pathol 2001; 193: 398-407.
- 33 Yanagita M, Oka M, Watabe T. et al. USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney. Biochem Biophys Res Commun 2004; 316: 490-500.
- 34 Laurikkala J, Kassai Y, Pakkasjarvi L. et al. Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Dev Biol 2003; 264: 91-105.
- 35 Charite J, McFadden DG, Merlo G. et al. Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer. Genes Dev 2001; 15: 3039-3049.
- 36 Song C, Hiipakka RA, Kokontis JM. et al. Ubiquitous receptor: structures, immunocytochemical localization, and modulation of gene activation by receptors for retinoic acids and thyroid hormones. Ann NY Acad Sci 1995; 761: 38-49.
- 37 Blaschke F, Leppanen O, Takata Y. et al. Liver X receptor agonists suppress vascular smooth muscle cell proliferation and inhibit neointima formation in balloon- injured rat carotid arteries. Circ Res 2004; 95: e110-123.
- 38 Goel A, Janknecht R. Concerted activation of ETS protein ER81 by p160 coactivators, the acetyltransferase p300 and the receptor tyrosine kinase HER2/Neu. J Biol Chem 2004; 279: 14909-14916.
- 39 Holla VR, Mann JR, Shi Q. et al. Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer. J Biol Chem 2006; 281: 2676-2682.
- 40 Liu D, Jia H, Holmes DI. et al. Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1. Arterioscler Thromb Vasc Biol 2003; 23: 2002-2007.
- 41 Huang N, Miller WL. Cloning of factors related to HIV-inducible LBP proteins that regulate steroidogenic factor-1-independent human placental transcription of the cholesterol side-chain cleavage enzyme, P450scc. J Biol Chem 2000; 275: 2852-2858.
- 42 Raghunath PN, Sidhu GS, Coon HC. et al. Interferons upregulate the expression of laminin and its receptor LBP-32 in cultured cells. J Biol Regul Homeost Agents 1993; 07: 22-30.
- 43 Lee TH, Wisniewski HG, Vilcek J. A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44. J Cell Biol 1992; 116: 545-557.
- 44 Wisniewski HG, Vilcek J. TSG-6: an IL-1/TNF-inducible protein with anti-inflammatory activity. Cytokine Growth Factor Rev 1997; 08: 143-156.
- 45 Ye L, Mora R, Akhayani N. et al. Growth factor and cytokine-regulated hyaluronan-binding protein TSG-6 is localized to the injury-induced rat neointima and confers enhanced growth in vascular smooth muscle cells. Circ Res 1997; 81: 289-296.
- 46 Zigrino P, Drescher C, Mauch C. Collagen-induced proMMP-2 activation by MT1-MMP in human dermal fibroblasts and the possible role of alpha2beta1 integrins. Eur J Cell Biol 2001; 80: 68-77.
- 47 Nagase H, Barrett AJ, Woessner Jr JF. Nomenclature and glossary of the matrix metalloproteinases. Matrix (Suppl) 1992; 01: 421-424.
- 48 Doronzo G, Russo I, Mattiello L. et al Homocysteine rapidly increases matrix metalloproteinase-2 expression and activity in cultured human vascular smooth muscle cells. Role of phosphatidyl inositol 3-kinase and mitogen activated protein kinase pathways. Thromb Haemost 2005; 94: 1285-1293.
- 49 Ye S. Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovasc Res 2006; 69: 636-645.
- 50 Natoli AK, Medley TL, Ahimastos AA. et al. Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression. Hypertension 2005; 46: 1129-1134.
- 51 Nishimura K, Ikebuchi M, Kanaoka Y. et al. Relationships between matrix metalloproteinases and tissue inhibitor of metalloproteinases in the wall of abdominal aortic aneurysms. Int Angiol 2003; 22: 229-238.
- 52 Pannu H, Kim DH, Guo D. et al. The role of MMP-2 and MMP-9 polymorphisms in sporadic intracranial aneurysms. J Neurosurg 2006; 105: 418-423.
- 53 Badier-Commander C, Verbeuren T, Lebard C. et al. Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. J Pathol 2000; 192: 105-112.
- 54 Chung ER, Miller R.K.. E.J. Isolation of three collagenous components of probable basement membrane origin from several tissues. Biochem Biophys Res Commun 1976; 71: 1167-1174.
- 55 Engel J, Furthmayr H, Odermatt E. et al. Structure and macromolecular organization of type VI collagen. Ann NY Acad Sci 1985; 460: 25-37.
- 56 Klewer SE, Krob SL, Kolker SJ. et al. Expression of type VI collagen in the developing mouse heart. Dev Dyn 1998; 211: 248-255.
- 57 Chakravarti S, Magnuson T.. Localization of mouse lumican (keratan sulfate proteoglycan) to distal chromosome 10. Mamm Genome 1995; 06: 367-368.
- 58 Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998; 93: 741-753.
- 59 Davey MG, James J, Paton IR. et al. Analysis of talpid( 3) and wild-type chicken embryos reveals roles for hedgehog signalling in development of the limb bud vasculature. Dev Biol 2007; 301: 155-165.
- 60 Lawson ND, Vogel AM, Weinstein BM. sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 2002; 03: 127-136.