The presence of toxic chemicals in various forms of environmental pollution has been associated with an increase in the extent and severity of vascular diseases. However, little is known about the cellular and molecular mechanisms by which specific vascular toxicants alter the structural and functional integrity of the blood vessel wall. The present studies were designed to test the hypothesis that exposure to allylamine and benzo(a)pyrene, toxic environmental contaminants, result in the phenotypic modulation of vascular smooth muscle cells. The modulation of smooth muscle cells from a contractile to a synthetic phenotype is in turn associated with enhanced cellular proliferation and the formation of lesions that resemble those found in atherosclerotic tissue. The effects of allylamine and benzo(a)pyrene will be evaluated in atherosclerosis-susceptible and non-susceptible animal classes. The structural integrity of the vessels in situ will be evaluated after subchronic exposure to the toxicants. Aortic smooth muscle cells obtained from control or treated animals will be established in primary culture and characterized by various morphological, biochemical and functional criteria. Confluent cultures of smooth muscle cells in the contractile state will be distinguished from synthetic cells by their spindle shape and preponderance of myofilaments as determined by light and electron microscopy. The synthetic and proliferative capabilities of the cells will be evaluated by measuring DNA and collagen synthesis using radiolabeled substrates as a function to time in culture. The status of the phosphoinositide system will be evaluated to determine if alterations in turnover are correlated with enhanced proliferative capacity. Cytoskeletal organization ornithine decarboxylase activity and phosphoprotein profile will also be evaluated. The responsiveness of smooth muscle cells to angiotension II and norepinephrine will be examined as a function of time to assess the functional status of the cells. The proposed studies will provide information regarding the cellular alterations associated with chemically-induced vascular injury. Ultimately, this information can be used to better understand the role that exposure to ubiquitous environmental contaminants plays in the development of atherosclerosis and other pathological changes of the vascular wall.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Toxicology Subcommittee 2 (TOX)
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Texas A&M University
Schools of Medicine
College Station
United States
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Ramos, Kenneth S; Stribinskis, Vilius; Steffen, Marlene C et al. (2013) Albumin-like proteins are critical regulators of vascular redox signaling. Oxid Med Cell Longev 2013:628615
Montoya-Durango, Diego E; Ramos, Kenneth S (2012) HPV E7 viral oncoprotein disrupts transcriptional regulation of L1Md retrotransposon. FEBS Lett 586:102-6
Williams, E Spencer; Wilson, Emily; Ramos, Kenneth S (2012) NF-?B and matrix-dependent regulation of osteopontin promoter activity in allylamine-activated vascular smooth muscle cells. Oxid Med Cell Longev 2012:496540
Ramos, Kenneth S; Montoya-Durango, Diego E; Teneng, Ivo et al. (2011) Epigenetic control of embryonic renal cell differentiation by L1 retrotransposon. Birth Defects Res A Clin Mol Teratol 91:693-702
Nanez, Adrian; Ramos, Irma N; Ramos, Kenneth S (2011) A mutant Ahr allele protects the embryonic kidney from hydrocarbon-induced deficits in fetal programming. Environ Health Perspect 119:1745-53
Teneng, Ivo; Montoya-Durango, Diego E; Quertermous, James L et al. (2011) Reactivation of L1 retrotransposon by benzo(a)pyrene involves complex genetic and epigenetic regulation. Epigenetics 6:355-67
Montoya-Durango, D E; Ramos, K S (2010) L1 retrotransposon and retinoblastoma: molecular linkages between epigenetics and cancer. Curr Mol Med 10:511-21
Montoya-Durango, Diego E; Liu, Yongqing; Teneng, Ivo et al. (2009) Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins. Mutat Res 665:20-8
Ramos, Kenneth S (2009) H-RAS controls phenotypic profiles of vascular smooth muscle cells and the pathogenesis of vascular proliferative disorders. Circ Res 104:1139-41
Zhang, Yong; Ramos, Kenneth S (2008) The development of abdominal aortic aneurysms in mice is enhanced by benzo(a)pyrene. Vasc Health Risk Manag 4:1095-102

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