title: Signaling pathways for arsenic-stimulated vascular endothelial growth factor-a expression in primary vascular smooth muscle cells.
abstract: Chronic arsenic exposure is associated with an increased risk for cancer, cardiovascular disease (including ischemic heart disease and hypertension), peripheral vascular disease, and diabetes. Arsenic causes blood vessel growth and remodeling in vivo and cell specific, dose-dependent induction vascular endothelial growth factor-A (VEGF), which is essential for both processes. The current study examined the hypothesis that low, environmentally relevant levels of trivalent arsenic (AsIII) activate discrete signaling pathways in vascular smooth muscle cells (SMC) to induce expression of VEGF. AsIII caused a progressive increase in VEGF mRNA levels over a 48 h period in primary porcine SMC with a threshold of 1-2.5 microM. VEGF protein levels increased with a similar concentration dependence and time course. Hypoxia inducible factor-1alpha (HIF-1alpha) protein and mRNA levels also increased in response to AsIII. However, unlike the response to an iron chelator, AsIII-induced VEGF was not inhibited by siRNA directed toward HIF-1alpha. Instead, a novel protein kinase C, PKCdelta, was activated by AsIII to induce VEGF and stabilize HIF-1alpha. Consistent with this activation, AsIII caused coordinate increases in the levels of the intracellular second messenger diacyglycerol (DAG). These data suggest that AsIII induced divergent signaling pathways in SMCs that lead to independent increases in VEGF expression and HIF-1alpha signaling. However, these pathways both require initial increases in DAG levels and PKC activity.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Nicole V
authors.initials: NV
authors.lastname: Soucy
authors.forename: Linda R
authors.initials: LR
authors.lastname: Klei
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Mayka
authors.forename: Aaron
authors.initials: A
authors.lastname: Barchowsky
mesh_terms: D000818:Animals; D001151:Arsenic / Q000737:chemistry / Q000633:toxicity*; D002614:Chelating Agents; D004305:Dose-Response Relationship, Drug; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012307:Risk Factors; D015290:Second Messenger Systems; D015398:Signal Transduction; D013552:Swine; D014157:Transcription Factors / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D002614:Chelating Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D001151:Arsenic