Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury.
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.
Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA David.Brott@astrazeneca.com.
David A
DA
Brott
Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA.
Anne
A
Katein
Safety Assessment, Pathology, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
Heath
H
Thomas
Drug Safety Research & Development, Pfizer Worldwide Research & Development, Groton, Connecticut, USA.
Michael
M
Lawton
BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
Robert R
RR
Montgomery
Department of Environmental Health Sciences, The University of Michigan, Ann Arbor, Michigan, USA.
Rudy J
RJ
Richardson
Drug Safety Sciences, Janssen Pharmaceuticals, Spring House, Pennsylvania, USA.
Calvert S
CS
Louden
D000284:Administration, Oral; D000577:Amides / Q000009:adverse effects; D000818:Animals; D001577:Benzophenones / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004298:Dopamine / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D018818:Fenoldopam / Q000009:adverse effects; D008297:Male; D018962:Phlebotomy; D011498:Protein Precursors / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar; D057772:Vascular System Injuries / Q000209:etiology / Q000473:pathology*; D014841:von Willebrand Factor
D000577:Amides; D001577:Benzophenones; D015415:Biomarkers; D011498:Protein Precursors; C095007:Zeneca ZD 6169; D014841:von Willebrand Factor; C067003:von Willebrand factor propolypeptide; D018818:Fenoldopam; D004298:Dopamine
DDAVP.; DIVI; LPS; VWF; VWFpp; activation; biomarker; dog; endothelial cell; perturbation; rat