Neovascularization and Angiogenic Gene Expression Following Chronic Arsenic Exposure in Mice

Abstract

Exposure to arsenic in drinking water increases incidence of cardiovascular diseases. However, the basic mechanisms and genetic changes that promote these diseases are unknown. This study investigated the effects of chronic arsenic exposure on vessel growth and expression of angiogenic and tissue remodeling genes in cardiac tissues. Male mice were exposed to low to moderately high levels of arsenite (AsIII) for 5, 10, or 20 wk in their drinking water. Vessel growth in Matrigel implants was tested during the last 2 wk of each exposure period. Implant vascularization increased in mice exposed to 5-500 ppb AsIII for 5 wk. Similar increases were seen following exposure to 50-250 ppb of AsIII over 20 wk, but the response to 500 ppb decreased with time. RT-PCR analysis of cardiac mRNA revealed differential expression of angiogenic or tissue remodeling genes, such as vascular endothelial cell growth factor (VEGF), VEGF receptors, plasminogen activator inhibitor-1, endothelin-1, and matrix metalloproteinase-9, which varied with time or amount of exposure. VEGF receptor mRNA and cardiac microvessel density were reduced by exposure to 500 ppb AsIII for 20 wk. These data demonstrate differential concentration and time-dependent effects of chronic arsenic exposure on cardiovascular phenotype and vascular remodeling that may explain the etiology for AsIII-induced disease.

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

“…The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration was observed in Matrigel plugs implanted in C57BL/6 mice following 5 week exposures to 5-500 ppb arsenic (Soucy et al, 2005). Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver.…”

“…This limitation is confounded by the current bias that intact rodent models are insensitive to the health effects of arsenic. The vascular effects of arsenic are an exception since vascular activation and dysfunction occur in mice exposed to low ppb levels of arsenic (Kamat et al, 2005;Liu et al, 2006;Soucy et al, 2003;Soucy et al, 2005). The importance of identifying in vivo endpoints that can be used to test for the vascular effects of low to moderate arsenic exposures is underscored by the multiple dose-dependent mechanisms elicited by arsenic exposures.…”

“…Thus endothelial cells generate the angiogenic response, but they cannot complete vessel maturation without recruitment of pericytes and smooth muscle cells in a process called vascular myogenesis (Ricousse-Roussanne et al, 2004;Carmeliet, 2000). Pathogenic endothelial cell activation and angiogenesis in rodent models are sensitive to low, environmentally relevant arsenic exposures (Soucy et al, 2003;Soucy et al, 2005;Kamat et al, 2005). Arsenic stimulates the angiogenic process in cultured cells and neovascularization in vivo (Barchowsky et al, 1996;Kao et al, 2003;Kamat et al, 2005;Liu et al, 2006;Soucy et al, 2003;Soucy et al, 2005).…”

“…Pathogenic endothelial cell activation and angiogenesis in rodent models are sensitive to low, environmentally relevant arsenic exposures (Soucy et al, 2003;Soucy et al, 2005;Kamat et al, 2005). Arsenic stimulates the angiogenic process in cultured cells and neovascularization in vivo (Barchowsky et al, 1996;Kao et al, 2003;Kamat et al, 2005;Liu et al, 2006;Soucy et al, 2003;Soucy et al, 2005). However, this stimulation occurs only at low to moderate concentrations of arsenic (5-500 ppb in vivo, 0.1-5.0 μM in cell culture; (Barchowsky et al, 1996;Kao et al, 2003;Soucy et al, 2003;Soucy et al, 2005)).…”

“…Arsenic stimulates the angiogenic process in cultured cells and neovascularization in vivo (Barchowsky et al, 1996;Kao et al, 2003;Kamat et al, 2005;Liu et al, 2006;Soucy et al, 2003;Soucy et al, 2005). However, this stimulation occurs only at low to moderate concentrations of arsenic (5-500 ppb in vivo, 0.1-5.0 μM in cell culture; (Barchowsky et al, 1996;Kao et al, 2003;Soucy et al, 2003;Soucy et al, 2005)). Concentrations of arsenic above 5 μM are toxic to confluent endothelial cells and limit tube formation in culture (Barchowsky et al, 1996;Roboz et al, 2000).…”