Gene Environment Interactions and Vascular Lesions

  • Quentin FeltyEmail author


Despite the extensive research in the field of tumor angiogenesis, the complex interaction of genes with environmental factors is not yet understood in terms of development and aggressiveness of vascular lesions in different human tumor types. Environmental risk factors such as tobacco smoke, alcohol, xenobiotics, arsenic, and air pollutants are the exposures studied most frequently for interactions with genetic polymorphisms in cancer. To date, results from the literature show no direct studies of angiogenic gene environment interactions. However, it is important to study angiogenic gene environment interactions because of the influence that vascular lesions have on the invasiveness of cancer. In this chapter, we review the literature to determine the possible role of angiogenic gene environment interactions in vascular lesion formation. We have focused our efforts using mainly estrogenic compounds as the model to describe the role of gene environment interactions in the pathogenesis of vascular lesions.


Environmental estrogens Oxidative stress Genetic susceptibility Angiogenesis 


  1. Arzuaga X, Reiterer G, Majkova Z, Kilgore MW, Toborek M, Hennig B 2007 PPARalpha ligands reduce PCB-induced endothelial activation: possible interactions in inflammation and atherosclerosis. Cardiovasc Toxicol 7:264–272PubMedCrossRefGoogle Scholar
  2. Barchowsky A, Roussel RR, Klei LR, James PE, Ganju N, Smith KR, Dudek EJ 1999 Low levels of arsenic trioxide stimulate proliferative signals in primary vascular cells without activating stress effector pathways. Toxicol Appl Pharmacol 159:65–75PubMedCrossRefGoogle Scholar
  3. Basu P, Ghosh RN, Grove LE, Klei L, Barchowsky A 2008 Angiogenic potential of 3-nitro-4-hydroxy benzene arsonic Acid (roxarsone). Environ Health Perspect 116:520–523PubMedCrossRefGoogle Scholar
  4. Behl C, Skutella T, Lezoualch F, Post A, Widmann M, Newton CJ, Holsboer F 1997 Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 51:535–541PubMedGoogle Scholar
  5. Benditt EP, Benditt JM 1973 Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci USA 70:1753–1756PubMedCrossRefGoogle Scholar
  6. Bocchinfuso WP, Hively WP, Couse JF, Varmus HE, Korach KS 1999 A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha. Cancer Res 59:1869–1876PubMedGoogle Scholar
  7. Boehm M, Nabel EG 2003 The cell cycle and cardiovascular diseases. Prog Cell Cycle Res 5:19–30PubMedGoogle Scholar
  8. Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, Byun HM, Jiang J, Marinelli B, Pesatori AC, Bertazzi PA, Yang AS 2007 Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67:876–880PubMedCrossRefGoogle Scholar
  9. Bredow S, Falgout MM, March TH, Yingling CM, Malkoski SP, Aden J, Bedrick EJ, Lewis JL, Divine KK 2007 Subchronic inhalation of soluble manganese induces expression of hypoxia-associated angiogenic genes in adult mouse lungs. Toxicol Appl Pharmacol 221:148–157PubMedCrossRefGoogle Scholar
  10. Buteau-Lozano H, Velasco G, Cristofari M, Balaguer P, Perrot-Applanat M 2008 Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism. J Endocrinol 196:399–412PubMedCrossRefGoogle Scholar
  11. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E 1998 Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490PubMedCrossRefGoogle Scholar
  12. Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn ME, Shaul PW 2002 ERbeta has nongenomic action in caveolae. Mol Endocrinol 16:938–946PubMedCrossRefGoogle Scholar
  13. Channon KM 2004 Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med 14:323–327PubMedCrossRefGoogle Scholar
  14. Charlier CJ, Albert AI, Zhang L, Dubois NG, Plomteux GJ 2004 Polychlorinated biphenyls contamination in women with breast cancer. Clin Chim Acta 347:177–181PubMedCrossRefGoogle Scholar
  15. Chen Y, Jin X, Zeng Z, Liu W, Wang B, Wang H 2008 Estrogen-replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing SDF-1 and estrogen receptor expression. Microvasc Res 77(2):71–77PubMedCrossRefGoogle Scholar
  16. Cheng JJ, Chao YJ, Wang DL 2002 Cyclic strain activates redox-sensitive proline-rich tyrosine kinase 2 (PYK2) in endothelial cells. J Biol Chem 277:48152–48157PubMedCrossRefGoogle Scholar
  17. Cullis ER, Kalber TL, Ashton SE, Cartwright JE, Griffiths JR, Ryan AJ, Robinson SP 2006 Tumour overexpression of inducible nitric oxide synthase (iNOS) increases angiogenesis and may modulate the anti-tumour effects of the vascular disrupting agent ZD6126. Microvasc Res 71:76–84PubMedCrossRefGoogle Scholar
  18. Donovan D, Brown NJ, Bishop ET, Lewis CE 2001 Comparison of three in vitro human ‘angiogenesis’ assays with capillaries formed in vivo. Angiogenesis 4:113–121PubMedCrossRefGoogle Scholar
  19. DuMond JW, Jr, Singh KP, Roy D 2001 Regulation of the growth of mouse Leydig cells by the inactive stereoisomer, 17alpha-estradiol: lack of correlation between the elevated expression of ERalpha and difference in sensitivity to estradiol isomers. Oncol Rep 8:899–902PubMedGoogle Scholar
  20. Dumortier J, Streblow DN, Moses AV, Jacobs JM, Kreklywich CN, Camp D, Smith RD, Orloff SL, Nelson JA 2008 Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J Virol 82:6524–6535PubMedCrossRefGoogle Scholar
  21. Eum SY, Lee YW, Hennig B, Toborek M 2004 VEGF regulates PCB 104-mediated stimulation of permeability and transmigration of breast cancer cells in human microvascular endothelial cells. Exp Cell Res 296:231–244PubMedCrossRefGoogle Scholar
  22. Felsch JS, Cachero TG, Peralta EG 1998 Activation of protein tyrosine kinase PYK2 by the m1 muscarinic acetylcholine receptor. Proc Natl Acad Sci USA 95:5051–5056PubMedCrossRefGoogle Scholar
  23. Felty Q 2006 Estrogen-induced DNA synthesis in vascular endothelial cells is mediated by ROS signaling. BMC Cardiovasc Disord 6:16PubMedCrossRefGoogle Scholar
  24. Felty Q, Porther N 2008 Estrogen-induced redox sensitive Id3 signaling controls the growth of vascular cells. Atherosclerosis 198:12–21PubMedCrossRefGoogle Scholar
  25. Felty Q, Singh KP, Roy D 2005a Estrogen-induced G(1)/S transition of G(0)-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene 24:4883–4893PubMedCrossRefGoogle Scholar
  26. Felty Q, Xiong WC, Sun D, Sarkar S, Singh KP, Parkash J, Roy D 2005b Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers. Biochemistry 44:6900–6909PubMedCrossRefGoogle Scholar
  27. Folkman J 1995 Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31PubMedCrossRefGoogle Scholar
  28. Folkmann JK, Risom L, Hansen CS, Loft S, Moller P 2007 Oxidatively damaged DNA and inflammation in the liver of dyslipidemic ApoE–/– mice exposed to diesel exhaust particles. Toxicology 237:134–144PubMedCrossRefGoogle Scholar
  29. Ghilardi G, Biondi ML, Mangoni J, Leviti S, DeMonti M, Guagnellini E, Scorza R 2001 Matrix metalloproteinase-1 promoter polymorphism 1G/2G is correlated with colorectal cancer invasiveness. Clin Cancer Res 7:2344–2346PubMedGoogle Scholar
  30. Haas E, Meyer MR, Schurr U, Bhattacharya I, Minotti R, Nguyen HH, Heigl A, Lachat M, Genoni M, Barton M 2007 Differential effects of 17beta-estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis. Hypertension 49:1358–1363PubMedCrossRefGoogle Scholar
  31. Hennig B, Hammock BD, Slim R, Toborek M, Saraswathi V, Robertson LW 2002a PCB-induced oxidative stress in endothelial cells: modulation by nutrients. Int J Hyg Environ Health 205:95–102PubMedCrossRefGoogle Scholar
  32. Hennig B, Meerarani P, Slim R, Toborek M, Daugherty A, Silverstone AE, Robertson LW 2002b Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. Toxicol Appl Pharmacol 181:174–183PubMedCrossRefGoogle Scholar
  33. Hong CC, Ambrosone CB, Ahn J, Choi JY, McCullough ML, Stevens VL, Rodriguez C, Thun MJ, Calle EE 2007 Genetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 16:1784–1794PubMedCrossRefGoogle Scholar
  34. Hornstein I, Alcover A, Katzav S 2004 Vav proteins, masters of the world of cytoskeleton organization. Cell Signal 16:1–11PubMedCrossRefGoogle Scholar
  35. Huang RP, Wu JX, Fan Y, Adamson ED 1996 UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol 133:211–220PubMedCrossRefGoogle Scholar
  36. Hyder SM, Stancel GM 1999 Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins. Mol Endocrinol 13:806–811PubMedCrossRefGoogle Scholar
  37. Iughetti P, Suzuki O, Godoi PH, Alves VA, Sertie AL, Zorick T, Soares F, Camargo A, Moreira ES, di LC, Moreira-Filho CA, Simpson A, Oliva G, Passos-Bueno MR 2001 A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma. Cancer Res 61:7375–7378PubMedGoogle Scholar
  38. Kanda N, Watanabe S 2004 17beta-estradiol stimulates the growth of human keratinocytes by inducing cyclin d2 expression. J Invest Dermatol 123:319–328PubMedCrossRefGoogle Scholar
  39. Kao YH, Yu CL, Chang LW, Yu HS 2003 Low concentrations of arsenic induce vascular endothelial growth factor and nitric oxide release and stimulate angiogenesis in vitro. Chem Res Toxicol 16:460–468PubMedCrossRefGoogle Scholar
  40. Kim-Schulze S, McGowan KA, Hubchak SC, Cid MC, Martin MB, Kleinman HK, Greene GL, Schnaper HW 1996 Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells. Circulation 94:1402–1407PubMedCrossRefGoogle Scholar
  41. Klei LR, Barchowsky A 2008 Positive signaling interactions between arsenic and ethanol for angiogenic gene induction in human microvascular endothelial cells. Toxicol Sci 102:319–327PubMedCrossRefGoogle Scholar
  42. Konac E, Onen HI, Metindir J, Alp E, Biri AA, Ekmekci A 2007 An investigation of relationships between hypoxia-inducible factor-1 alpha gene polymorphisms and ovarian, cervical and endometrial cancers. Cancer Detect Prev 31:102–109PubMedCrossRefGoogle Scholar
  43. Laurent G, Solari F, Mateescu B, Karaca M, Castel J, Bourachot B, Magnan C, Billaud M, Mechta-Grigoriou F 2008 Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling. Cell Metab 7:113–124PubMedCrossRefGoogle Scholar
  44. Lim EJ, Smart EJ, Toborek M, Hennig B 2007 The role of caveolin-1 in PCB77-induced eNOS phosphorylation in human-derived endothelial cells. Am J Physiol Heart Circ Physiol 293:H3340–H3347PubMedCrossRefGoogle Scholar
  45. Mehendale R, Hibbard J, Fazleabas A, Leach R 2007 Placental angiogenesis markers sFlt-1 and PlGF: response to cigarette smoke. Am J Obstet Gynecol 197:363–365PubMedCrossRefGoogle Scholar
  46. Nematbakhsh M, Ghadesi M, Hosseinbalam M, Khazaei M, Gharagozlo M, Dashti G, Rajabi P, Rafieian S 2008 Oestrogen promotes coronary angiogenesis even under normoxic conditions. Basic Clin Pharmacol Toxicol 103:273–277PubMedCrossRefGoogle Scholar
  47. Okabe S, Fukuda S, Kim YJ, Niki M, Pelus LM, Ohyashiki K, Pandolfi PP, Broxmeyer HE 2005 Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1. Blood 105:474–480PubMedCrossRefGoogle Scholar
  48. Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, Hirata K, Yasui H, Sakurai H, Yoshida Y, Masada M, Yokoyama M 2002 Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 110:331–340PubMedGoogle Scholar
  49. Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P, Mendelsohn ME 2002 Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 90:1087–1092PubMedCrossRefGoogle Scholar
  50. Park KS, Mok JW, Ko HE, Tokunaga K, Lee MH 2002 Polymorphisms of tumour necrosis factors A and B in breast cancer. Eur J Immunogenet 29:7–10PubMedCrossRefGoogle Scholar
  51. Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, Zeiher AM, Dimmeler S 2007 SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 21:2644–2658PubMedCrossRefGoogle Scholar
  52. Pu M, Akhand AA, Kato M, Hamaguchi M, Koike T, Iwata H, Sabe H, Suzuki H, Nakashima I 1996 Evidence of a novel redox-linked activation mechanism for the Src kinase which is independent of tyrosine 527-mediated regulation. Oncogene 13:2615–2622PubMedGoogle Scholar
  53. Ramadass P, Meerarani P, Toborek M, Robertson LW, Hennig B 2003 Dietary flavonoids modulate PCB-induced oxidative stress, CYP1A1 induction, and AhR-DNA binding activity in vascular endothelial cells. Toxicol Sci 76:212–219PubMedCrossRefGoogle Scholar
  54. Ramos KS, Chacon E, Acosta D Jr 1996 Toxic responses of the heart and vascular systems. In: Klaassen CD, ed. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 5th ed. New York: McGraw-Hill; 487–527Google Scholar
  55. Roy D, Abul-Hajj YJ 1997 Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene. Carcinogenesis 18:1247–1249PubMedCrossRefGoogle Scholar
  56. Roy D, Cai Q 2002 Estrogen, immunoactivation, gene damage, and development of breast, endometrial, ovarian, prostate, and testicular cancers. Recent Res Devel Steroid Biochem Mol Biol 3:1–32Google Scholar
  57. Roy D, Floyd RA, Liehr JG 1991 Elevated 8-hydroxydeoxyguanosine levels in DNA of diethylstilbestrol-treated Syrian hamsters: covalent DNA damage by free radicals generated by redox cycling of diethylstilbestrol. Cancer Res 51:3882–3885PubMedGoogle Scholar
  58. Roy D, Liehr JG 1999 Estrogen, DNA damage and mutations. Mutat Res 424:107–115PubMedCrossRefGoogle Scholar
  59. Sasaki H, Ray PS, Zhu L, Galang N, Maulik N 2000 Oxidative stress due to hypoxia/reoxygenation induces angiogenic factor VEGF in adult rat myocardium: possible role of NFkappaB. Toxicology 155:27–35PubMedCrossRefGoogle Scholar
  60. Schieffer B, Drexler H, Ling BN, Marrero MB 1997 G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras. Am J Physiol 272:C2019–C2030PubMedGoogle Scholar
  61. Schneider BP, Radovich M, Sledge GW, Robarge JD, Li L, Storniolo AM, Lemler S, Nguyen AT, Hancock BA, Stout M, Skaar T, Flockhart DA 2008 Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat 111:157–163PubMedCrossRefGoogle Scholar
  62. Schwartz SM, Murry CE 1998 Proliferation and the monoclonal origins of atherosclerotic lesions. Annu Rev Med 49:437–460PubMedCrossRefGoogle Scholar
  63. Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, Strange RC, Hutchinson PE, Osborne JE, Lear JT, Smith AG, Hutchinson IV 2002 Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359:397–401PubMedCrossRefGoogle Scholar
  64. Shortt AJ, Howell K, OBrien C, McLoughlin P 2004 Chronic systemic hypoxia causes intra-retinal angiogenesis. J Anat 205:349–356PubMedCrossRefGoogle Scholar
  65. Sipka S, Eum SY, Son KW, Xu S, Gavalas VG, Hennig B, Toborek M 2008 Oral administration of PCBs induces proinflammatory and prometastatic responses. Environ Toxicol Pharmacol 25:251–259PubMedCrossRefGoogle Scholar
  66. Stier CT Jr, Chander PN, Rosenfeld L, Powers CA 2003 Estrogen promotes microvascular pathology in female stroke-prone spontaneously hypertensive rats. Am J Physiol Endocrinol Metab 285:E232–E239PubMedGoogle Scholar
  67. Stork S, van der Schouw YT, Grobbee DE, Bots ML 2004 Estrogen, inflammation and cardiovascular risk in women: a critical appraisal. Trends Endocrinol Metab 15:66–72PubMedCrossRefGoogle Scholar
  68. Takada Y, Kato C, Kondo S, Korenaga R, Ando J 1997 Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress. Biochem Biophys Res Commun 240:737–741PubMedCrossRefGoogle Scholar
  69. Tan W, Bailey AP, Shparago M, Busby B, Covington J, Johnson JW, Young E, Gu JW 2007 Chronic alcohol consumption stimulates VEGF expression, tumor angiogenesis and progression of melanoma in mice. Cancer Biol Ther 6:1211–1217PubMedCrossRefGoogle Scholar
  70. Tarantini L, Bonzini M, Apostoli P, Pegoraro V, Bollati V, Marinelli B, Cantone L, Rizzo G, Hou L, Schwartz J, Bertazzi PA, Baccarelli A 2009 Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117:217–222Google Scholar
  71. Tavolari S, Bucci L, Tomasi V, Guarnieri T 2006 Selected polychlorobiphenyls congeners bind to estrogen receptor alpha in human umbilical vascular endothelial (HUVE) cells modulating angiogenesis. Toxicology 218:67–74PubMedCrossRefGoogle Scholar
  72. Toda T, Leszczynski D, Kummerow F 1981 Vasculotoxic effects of dietary testosterone, estradiol, and cholesterol on chick artery. J Pathol 134:219–231PubMedCrossRefGoogle Scholar
  73. Tseng CH, Chong CK, Chen CJ, Tai TY 1997 Lipid profile and peripheral vascular disease in arseniasis-hyperendemic villages in Taiwan. Angiology 48:321–335PubMedCrossRefGoogle Scholar
  74. Vairaktaris E, Yapijakis C, Serefoglou Z, Derka S, Vassiliou S, Nkenke E, Vylliotis A, Spyridonidou S, Neukam FW, Schlegel KA, Patsouris E 2008 The interleukin-10 (-1082A/G) polymorphism is strongly associated with increased risk for oral squamous cell carcinoma. Anticancer Res 28:309–314PubMedGoogle Scholar
  75. Villablanca A, Lubahn D, Shelby L, Lloyd K, Barthold S 2004 Susceptibility to early atherosclerosis in male mice is mediated by estrogen receptor alpha. Arterioscler Thromb Vasc Biol 24:1055–1061PubMedCrossRefGoogle Scholar
  76. White RE, Han G, Dimitropoulou C, Zhu S, Miyake K, Fulton D, Dave S, Barman SA 2005 Estrogen-induced contraction of coronary arteries is mediated by superoxide generated in vascular smooth muscle. Am J Physiol Heart Circ Physiol 289:H1468–H1475PubMedCrossRefGoogle Scholar
  77. Wong HP, Yu L, Lam EK, Tai EK, Wu WK, Cho CH 2007 Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation. Toxicol Sci 97:279–287PubMedCrossRefGoogle Scholar
  78. Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM Jr, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, Koulen P, Simpkins JW 2004 Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci USA 101:4130–4135PubMedCrossRefGoogle Scholar
  79. Zhao T, Bokoch GM 2005 Critical role of proline-rich tyrosine kinase 2 in reversion of the adhesion-mediated suppression of reactive oxygen species generation by human neutrophils. J Immunol 174:8049–8055PubMedGoogle Scholar
  80. Zhu BQ, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, Cooke JP 2003 Second hand smoke stimulates tumor angiogenesis and growth. Cancer Cell 4:191–196PubMedCrossRefGoogle Scholar
  81. Zhu Y, Spitz MR, Lei L, Mills GB, Wu X 2001 A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility. Cancer Res 61:7825–7829PubMedGoogle Scholar

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© Springer Science+ Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Environmental and Occupational HealthFIU Stempel School of Public Health, Florida International UniversityMiamiUSA

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