Arsenic Requires Sphingosine-1-Phosphate Type 1 Receptors to Induce Angiogenic Genes and Endothelial Cell Remodeling

Abstract

Arsenic in drinking water is a major public health concern as it increases risk and incidence of cardiovascular disease and cancer. Arsenic exposure affects multiple vascular beds, promoting liver sinusoidal capillarization and portal hypertension, ischemic heart disease, peripheral vascular disease, and tumor angiogenesis. While Rac1-GTPase and NADPH oxidase activities are essential for arsenic-stimulated endothelial cell signaling for angiogenesis or liver sinusoid capillarization, the mechanism for initiating these effects is unknown. We found that arsenic-stimulated cell signaling and angiogenic gene expression in human microvascular endothelial cells were Pertussis toxin sensitive, indicating a G-protein coupled signaling pathway. Incubating human microvascular endothelial cells with the sphingosine-1-phosphate type 1 receptor (S1P 1 ) inhibitor VPC23019 or performing small interfering RNA knockdown of S1P 1 blocked arsenic-stimulated HMVEC angiogenic gene expression and tube formation, but did not affect induction of either HMOX1 or IL8. Liver sinusoidal endothelial cells (LSECs) defenestrate and capillarize in response to aging and environmental oxidant stresses. We found that S1P 1 was enriched on LSECs in vivo and in primary cell culture and that VPC23019 inhibited both sphingosine-1-phosphate-stimulated and arsenic-stimulated LSEC oxidant generation and defenestration. These studies identified novel roles for S1P 1 in mediating arsenic stimulation of both angiogenesis and pathogenic LSEC capillarization, as well as demonstrating a role for S1P 1 in mediating environmental responses in the liver vasculature, providing possible mechanistic insight into arsenic-induced vascular pathogenesis and disease.

R-Ras and Rac GTPase Cross-talk Regulates Hematopoietic Progenitor Cell Migration, Homing, and Mobilization

“…The cells were laid on top of Histopaque-1083 (Sigma) and centrifuged at 2000 rpm for 10 min at room temperature to obtain low density BM (LDBM) cells. Murine embryonic fibroblasts and human vascular endothelial cells (HMVECs) were obtained and cultured as described elsewhere (31,32).…”

Arsenic, Reactive Oxygen, and Endothelial Dysfunction

“…As III -induced pathophysiological remodeling of LSECs (defenestration/capillarization and platelet/endothelial cell adhesion molecule-1 expression) is also attenuated variously by Nox2ds-tat, genetic deletion of p47 phox and selective pharmacological inhibition of Rac1 (Straub et al, 2008). Furthermore, studies of human microvascular ECs and LSECs have revealed that As III activates a pertussis toxin-sensitive G protein (i.e., G i )-coupled pathway to induce Rac1 translocation (Straub et al, 2009) (Fig. 3).…”

“…3). Indeed, As III -induced angiogenic gene expression in human microvascular ECs is prevented by pharmacological blockade or siRNA knockdown of sphingosine-1-phosphate type 1 receptors (S1PR 1 ) (Straub et al, 2009), and blockade of S1PR 1 s prevents both S1P-and As III -induced ROS formation in LSECs (Straub et al, 2009). Pertussis toxinsensitive As III -induced differentiation of human mesenchymal stem cells, however, is unaffected by blockade of S1PR 1 s, but is prevented in a cumulative fashion by selective blockers of endothelin-1 type A and B receptors (Klei et al, 2013).…”

MicroRNA-200b Suppresses Arsenic-transformed Cell Migration by Targeting Protein Kinase Cα and Wnt5b-Protein Kinase Cα Positive Feedback Loop and Inhibiting Rac1 Activation

“…Previous studies showed that short term arsenic exposure causes Rac1 activation in endothelial cells and Rac1 activity is required for arsenic-stimulated endothelial cell remodeling and angiogenesis (46,47). However, whether Rac1 is activated in cells malignantly transformed by long term arsenic exposure and whether Rac1 plays a role in arsenic carcinogenesis are not clear.…”