E-Table 3
Up-regulated genes with implicated or putative roles in vascular smooth muscle or endothelial cell function and angiogenesis in FSHD muscle. * denotes genes that were differentially expressed in FSHD versus healthy people, but also showed a slight trend in the same direction for DM1 versus healthy people.
Gene / Role in vascular system / ReferencesGenes implicated in vascular smooth muscle or endothelial cell function and angiogenesis
ACTA2* / Recognized marker of vascular smooth muscle. Most abundant actin isoform in mature differentiated vascular smooth muscle, comprising up to 40% of total cellular protein. / (1)
CCN2 (CTGF) / Required for normal vascular development.
Induces angiogenesis in vivo.
Autocrine actions to promote endothelial migration, proliferation, and function. / (2)
CCN3/NOV / Expressed in vascular smooth muscle cells.
Pro-angiogenic for endothelial cells.
Induces angiogenesis in vivo
(associated with, and activates, Notch 1). / (3-6)
CD9 / Expressed in smooth muscle cells. / (7, 8)
CD44 / Expressed in vascular smooth muscle and endothelial cells.
Pro-angiogenic for endothelial cells.
Arteriogeneiss is severely impaired in CD44 null mice. / (9, 10)
Endoglin* / Membrane receptor expressed in endothelial cells.
Upregulated in activated endothelial cells.
Considered a marker for neovascularization,
required for normal vascular development. / (11-13)
Intercellular adhesion molecule 1 (CD54) / Expressed in vascular smooth muscle and endothelial cells.
Pro-angiogenic via a NO-dependent pathway.
Arteriogenesis is impaired in the absence of CD54 in a rabbit model. / (14, 15)
Melanoma cell adhesion molecule (MCAM) / Expression marker for smooth muscle and endothelium.
Upregulated by endothelial cell activation in culture and in neovascular endothelial cells in vivo.
Anti-MCAM monoclonal antibody inhibits angiogenesis / (16-18)
Microfibrillar associated protein 5 (MAGP-2) / Component of elastic fibers.
Immunolocalized in fetal muscle to endomysium, perimysium and walls of blood vessels.
Pro-angiogenic via a Jagged 1 pathway. Interacts with Jagged 1 (Notch 1 ligand), and increases rate of Jagged 1 shedding from cells. / (19, 20)
Microsomal epoxide hydrolase / Expressed in endothelial cells.
Upregulated in endothelial cells in response to shear stress. / (21, 22)
Phosphodiesterase 4B / Expressed in microvascular endothelial cells and vascular smooth muscle.
Pro-angiogenic via upregulation of endothelial cell migration. / (23-25)
Syndecan 2 / Required for normal angiogenesis in zebrafish.
Expressed in human endothelial and vascular smooth muscle.
Interacts with CCN2.
Putative role as coreceptor to assist in delivery of pro-angiogenic factors to cell surface receptors. / (26, 27)
Transgelin / One of the earliest markers of vascular smooth muscle differentiation. / (1)
Genes with putative roles in vascular smooth muscle or endothelial cell function and angiogenesis
IL-17D / Rhis cytokine (and its cognate receptor) are expressed in endothelial cells.
Upregulated during hyaluron-induced endothelial sprouting. / (28)
Jun D proto-oncogene / Upregulated in response to vascular injury.
Reduces tumor angiogenesis by protecting cells from oxidative stress. / (29, 30)
Profilin 2 / Induced in endothelial cells by shear stress.
Expressed more highly in arteries than veins. / (31)
TIMP2 / Expression increased in injured arteries in rats.
Inhibits endothelial cell proliferation in response to FGF-2 or VEGA-A stimulation in vitro. / (32, 33)
Thrombospondin / Secreted by vascular smooth muscle and endothelial cells.
Thrombospondin can be pro- or anti-angiogenic. / (34)
References
1. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 1995;75:487-517.
2. Chen Y, Abraham DJ, Shi-Wen X, et al. CCN2 (connective tissue growth factor) promotes fibroblast adhesion to fibronectin. Mol Biol Cell 2004;15:5635-5646.
3. Lin CG, Leu SJ, Chen N, et al. CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem 2003;278:24200-24208.
4. Lin CG, Chen CC, Leu SJ, Grzeszkiewicz TM, Lau LF. Integrin-dependent functions of the angiogenic inducer NOV (CCN3): Implication in wound healing. J Biol Chem 2005;280:8229-8237.
5. Perbal B. NOV (nephroblastoma overexpressed) and the CCN family of genes: Structural and functional issues. Mol Pathol 2001;54:57-79.
6. Ellis PD, Chen Q, Barker PJ, Metcalfe JC, Kemp PR. Nov gene encodes adhesion factor for vascular smooth muscle cells and is dynamically regulated in response to vascular injury. Arterioscler Thromb Vasc Biol 2000;20:1912-1919.
7. Lijnen HR, Lupu F, Collen D, Le Naour F, Boucheix C. CD9 gene deficiency does not affect smooth muscle cell migration and neointima formation after vascular injury in mice. Thromb Haemost 2000;83:956-961.
8. Nakamura Y, Handa K, Iwamoto R, Tsukamoto T, Takahasi M, Mekada E. Immunohistochemical distribution of CD9, heparin binding epidermal growth factor-like growth factor, and integrin alpha3beta1 in normal human tissues. J Histochem Cytochem 2001;49:439-444.
9. Savani RC, Cao G, Pooler PM, Zaman A, Zhou Z, DeLisser HM. Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. J Biol Chem 2001;276:36770-36778.
10. van Royen N, Voskuil M, Hoefer I, et al. CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization. Circulation 2004;109:1647-1652.
11. Fonsatti E, Del Vecchio L, Altomonte M, et al. Endoglin: An accessory component of the TGF-beta-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies. J Cell Physiol 2001;188:1-7.
12. Li DY, Sorensen LK, Brooke BS, et al. Defective angiogenesis in mice lacking endoglin. Science 1999;284:1534-1537.
13. Miller DW, Graulich W, Karges B, et al. Elevated expression of endoglin, a component of the TGF-beta-receptor complex, correlates with proliferation of tumor endothelial cells. Int J Cancer 1999;81:568-572.
14. Kevil CG, Orr AW, Langston W, et al. Intercellular adhesion molecule-1 (ICAM-1) regulates endothelial cell motility through a nitric oxide-dependent pathway. J Biol Chem 2004;279:19230-19238.
15. Hoefer IE, van Royen N, Rectenwald JE, et al. Arteriogenesis proceeds via ICAM-1/Mac-1- mediated mechanisms. Circ Res 2004;94:1179-1185.
16. Yan X, Lin Y, Yang D, et al. A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood 2003;102:184-191.
17. Bardin N, Anfosso F, Masse JM, et al. Identification of CD146 as a component of the endothelial junction involved in the control of cell-cell cohesion. Blood 2001;98:3677-3684.
18. Shih IM. The role of CD146 (mel-CAM) in biology and pathology. J Pathol 1999;189:4-11.
19. Gibson MA, Finnis ML, Kumaratilake JS, Cleary EG. Microfibril-associated glycoprotein-2 (MAGP-2) is specifically associated with fibrillin-containing microfibrils but exhibits more restricted patterns of tissue localization and developmental expression than its structural relative MAGP-1. J Histochem Cytochem 1998;46:871-886.
20. Nehring LC, Miyamoto A, Hein PW, Weinmaster G, Shipley JM. The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface. J Biol Chem 2005;280:20349-20355.
21. Coller JK, Fritz P, Zanger UM, et al. Distribution of microsomal epoxide hydrolase in humans: An immunohistochemical study in normal tissues, and benign and malignant tumours. Histochem J 2001;33:329-336.
22. Farin FM, Pohlman TH, Omiecinski CJ. Expression of cytochrome P450s and microsomal epoxide hydrolase in primary cultures of human umbilical vein endothelial cells. Toxicol Appl Pharmacol 1994;124:1-9.
23. Netherton SJ, Maurice DH. Vascular endothelial cell cyclic nucleotide phosphodiesterases and regulated cell migration: Implications in angiogenesis. Mol Pharmacol 2005;67:263-272.
24. Polson JB, Strada SJ. Cyclic nucleotide phosphodiesterases and vascular smooth muscle. Annu Rev Pharmacol Toxicol 1996;36:403-427.
25. Busch CJ, Liu H, Graveline AR, Bloch KD. Nitric oxide induces phosphodiesterase 4B expression in rat pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2005.
26. Chen E, Hermanson S, Ekker SC. Syndecan-2 is essential for angiogenic sprouting during zebrafish development. Blood 2004;103:1710-1719.
27. Essner JJ, Chen E, Ekker SC. Syndecan-2. Int J Biochem Cell Biol 2006;38:152-156.
28. Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol 2002;169:642-646Takahashi Y, Li L, Kamiyaro M, et al. Hyaluron fragments induce endothelial cell differentiation in CD44- and CXCL1/GRO1-dependent manner. J Biol Chem 2005; 280:24195-24204.
29. Miano JM, Vlasic N, Tota RR, Stemerman MB. Localization of fos and jun proteins in rat aortic smooth muscle cells after vascular injury. Am J Pathol 1993;142:715-724.
30. Gerald D, Berra E, Frapart YM, et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004;118:781-794.
31. Witke W. The role of profilin complexes in cell motility and other cellular processes. Trends Cell Biol 2004;14:461-469.
32. Hasenstab D, Forough R, Clowes AW. Plasminogen activator inhibitor type 1 and tissue inhibitor of metalloproteinases-2 increase after arterial injury in rats. Circ Res 1997;80:490-496.
33. Seo DW, Li H, Guedez L, et al. TIMP-2 mediated inhibition of angiogenesis: An MMP-independent mechanism. Cell 2003;114:171-180.
34. Esemuede N, Lee T, Pierre-Paul D, Sumpio BE, Gahtan V. The role of thrombospondin-1 in human disease. J Surg Res 2004;122:135-142.