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Toxicol Pathol. 2014 Jun;42(4):672-83. doi: 10.1177/0192623313518664. Epub 2014 Feb 4.

Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury.

Author information

1
Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA David.Brott@astrazeneca.com.
2
Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA.
3
Safety Assessment, Pathology, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
4
Drug Safety Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut, USA.
5
BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
6
Department of Environmental Health Sciences, The University of Michigan, Ann Arbor, Michigan, USA.
7
Drug Safety Sciences, Janssen Pharmaceuticals, Spring House, Pennsylvania, USA.

Abstract

Pharmacologically, vasoactive agents targeting endothelial and/or smooth muscle cells (SMC) are known to cause acute drug-induced vascular injury (DIVI) and the resulting pathology is due to endothelial cell (EC) perturbation, activation, and/or injury. Alteration in EC structure and/or function may be a critical event in vascular injury and, therefore, evaluation of the circulatory kinetic profile and secretory pattern of EC-specific proteins such as VWF and VWFpp could serve as acute vascular injury biomarkers. In rat and dog models of DIVI, this profile was determined using pharmacologically diverse agents associated with functional stimulation/perturbation (DDAVP), pathological activation (lipopolysaccharide [LPS]/endotoxin), and structural damage (fenoldopam [FD], dopamine [DA], and potassium channel opener (PCO) ZD6169). In rats, FD caused moderate DIVI and time-related increase in plasma VWF levels ∼33% while in control rats VWF increased ∼5%. In dogs, VWF levels transiently increased ∼30% when there was morphologic evidence of DIVI by DA or ZD6169. However, in dogs, VWFpp increased >60-fold (LPS) and >6-fold (DDAVP), respectively. This was in comparison to smaller dynamic 1.38-fold (LPS) and 0.54-fold (DDAVP) increases seen in plasma VWF. Furthermore, DA was associated with a dose-dependent increase in plasma VWFpp. In summary, VWF and VWFpp can discriminate between physiological and pathological perturbation, activation, and injury to ECs.

KEYWORDS:

DDAVP.; DIVI; LPS; VWF; VWFpp; activation; biomarker; dog; endothelial cell; perturbation; rat

PMID:
24499802
PMCID:
PMC4222990
DOI:
10.1177/0192623313518664
[Indexed for MEDLINE]
Free PMC Article

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