Microvascular dysfunction with increased vascular leakage response in mice systemically exposed to arsenic.
The mechanisms underlying cardiovascular disease induced by arsenic exposure are not completely understood. The objectives of this study were to investigate whether arsenic-fed mice have an increased vascular leakage response to vasoactive agents and whether enhanced type-2 protein phosphatase (PP2A) activity is involved in mustard oil-induced leakage. ICR mice were fed water or sodium arsenite (20 mg/kg) for 4 or 8 weeks. The leakage response to vasoactive agents was quantified using the Evans blue (EB) technique or vascular labeling with carbon particles. Increased EB leakage and high density of carbon-labeled microvessels were detected in arsenic-fed mice treated with mustard oil. Histamine induced significantly higher vascular leakage in arsenic-fed mice than in water-fed mice. Pretreatment with the PP2A inhibitor okadaic acid or the neurokinin 1 receptor (NK1R) blocker RP67580 significantly reduced mustard oil-induced vascular leakage in arsenic-fed mice. The protein levels of PP2Ac and NK1R were similar in both groups. PP2A activity was significantly higher in the arsenic-fed mice compared with the control group. These findings indicate that microvessels generally respond to vasoactive agents, and that the increased PP2A activity is involved in mustard oil-induced vascular leakage in arsenic-fed mice. Arsenic may initiate endothelial dysfunction, resulting in vascular leakage in response to vasoactive agents.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, Taiwan, jaychen@kmu.edu.tw.
Shih-Chieh
SC
Chen
Shin-Yin
SY
Huang
Chi-Yu
CY
Lu
Ya-Hung
YH
Hsu
Dean-Chuan
DC
Wang
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects*; D004423:Ear / Q000098:blood supply; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005070:Evans Blue / Q000378:metabolism; D006632:Histamine / Q000009:adverse effects; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009149:Mustard Plant / Q000009:adverse effects; D019319:Okadaic Acid / Q000494:pharmacology; D010938:Plant Oils / Q000009:adverse effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*; D053719:Tandem Mass Spectrometry; D014652:Vascular Diseases / Q000139:chemically induced* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000009:adverse effects
D018053:Arsenites; D004791:Enzyme Inhibitors; D054833:Isoindoles; D010938:Plant Oils; D018040:Receptors, Neurokinin-1; D017670:Sodium Compounds; D014662:Vasoconstrictor Agents; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D019319:Okadaic Acid; D005070:Evans Blue; C017947:sodium arsenite; D006632:Histamine; D054648:Protein Phosphatase 2; C027793:mustard oil