Evaluation of Plasma von Willebrand Factor as a Biomarker for Acute Arterial Damage in Rats

Newsholme, Stephen J.; Thudium, Douglas; Gossett, Kent A.; Watson, Erica S.; Schwartz, Lester W.

doi:10.1177/019262330002800508

Cited by 28 publications

(27 citation statements)

References 21 publications

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“…A variety of studies have utilized an elevated circulating von Willebrand factor Ag (vWF) concentration as a marker of endothelial cell injury in other organs in response to a variety of insults (1,6,13,19,28,35,37) including ischemia-reperfusion injury to the intestines (1). Therefore, we quantified circulating vWF in Sprageu-Dawley rats as a marker of renal endothelial injury after renal ischemia.…”

Section: Biochemical Evidence Of Renal Endothelial Injury During Ischmentioning

confidence: 99%

Injury of the renal microvascular endothelium alters barrier function after ischemia

Sutton

Mang²,

Campos³

et al. 2003

American Journal of Physiology-Renal Physiology

285

227

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The role of renal microvascular endothelial cell injury in the pathophysiology of ischemic acute renal failure (ARF) remains largely unknown. No consistent morphological alterations have been ascribed to the endothelium of the renal microvasculature as a result of ischemia-reperfusion injury. Therefore, the purpose of this study was to examine biochemical markers of endothelial injury and morphological changes in the renal microvascular endothelium in a rodent model of ischemic ARF. Circulating von Willebrand factor (vWF) was measured as a marker of endothelial injury. Twenty-four hours after ischemia, circulating vWF peaked at 124% over baseline values ( P = 0.001). The FVB-TIE2/GFP mouse was utilized to localize morphological changes in the renal microvascular endothelium. Immediately after ischemia, there was a marked increase in F-actin aggregates in the basal and basolateral aspect of renal microvascular endothelial cells in the corticomedullary junction. After 24 h of reperfusion, the pattern of F-actin staining was more similar to that observed under physiological conditions. In addition, alterations in the integrity of the adherens junctions of the renal microvasculature, as demonstrated by loss of localization in vascular endothelial cadherin immunostaining, were observed after 24 h of reperfusion. This observation temporally correlated with the greatest extent of permeability defect in the renal microvasculature as identified using fluorescent dextrans and two-photon intravital imaging. Taken together, these findings indicate that renal vascular endothelial injury occurs in ischemic ARF and may play an important role in the pathophysiology of ischemic ARF.

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Section: Biochemical Evidence Of Renal Endothelial Injury During Ischmentioning

confidence: 99%

Injury of the renal microvascular endothelium alters barrier function after ischemia

Sutton

Mang²,

Campos³

et al. 2003

American Journal of Physiology-Renal Physiology

285

227

View full text Add to dashboard Cite

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“…Dogs treated with a potassium channel opener (PCO) caused plasma vWF to increase as early as 3 hours postdosing (Brott et al, 2005b). This observation in conjunction with other reports raise the possibility that the transient 2-6-hour increase in circulating plasma vWF could be a reporter of endothelial cell activation/perturbation prior to morphologic evidence of vascular damage (Newsholme et al, 2000). However, plasma vWF values returned to baseline or lower 24 hours postdosing when vascular damage was confirmed histologically (Brott et al, 2005b).…”

Section: Vwf and Vwfppmentioning

confidence: 67%

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

et al. 2006

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In preclinical safety studies, drug-induced vascular injury can negatively impact candidate-drug selection because there are no obvious diagnostic markers for monitoring this pathology preclinically or clinically. Furthermore, our current understanding of the pathogenesis of this lesion is limited. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary target cells, smooth muscle (SMC) and endothelial cell (EC), are unknown. Evaluation of potential novel markers for clinical monitoring with a mechanistic underpinning would add value in risk assessment and risk management. This mini review focuses on the efforts and progress to identify diagnostic markers as well as understanding the mechanism of action in nonrodent drug-induced vascular injury.

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“…Histologic assessment of mesenteric arteries from rats was conducted only at the 24-hr time point because at shorter postdosing intervals, previous study data (Newsholme et al 2000) indicate that mesenteric arterial pathology induced by FD was an infrequent occurrence. Histologic lesions induced by FD in rats have been previously described (Kerns et al 1989a; Kerns, Arena, and Morgan 1989b; Yuhas et al 1985).…”

Section: Resultsmentioning

confidence: 99%

“…An exception is a study in a rat model of acute mesenteric arterial injury, using the dopaminergic vasodilator fenoldopam (FD). FD was associated with marginal and transient increases in plasma VWF during periods of arterial damage but a definitive conclusion could not be drawn because repeated venipuncture was also associated with a time-dependent increase in plasma VWF concentrations in saline-treated rats (Newsholme et al 2000). Because of this procedural-related increase in VWF associated with venipuncture in rats, interpretation was confounded and the increase in plasma VWF was attributed in part, to an acute phase inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of von Willebrand Factor and von Willebrand Factor Propeptide in Models of Vascular Endothelial Cell Activation, Perturbation, and/or Injury

et al. 2014

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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.

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Evaluation of Plasma von Willebrand Factor as a Biomarker for Acute Arterial Damage in Rats

Cited by 28 publications

References 21 publications

Injury of the renal microvascular endothelium alters barrier function after ischemia

Injury of the renal microvascular endothelium alters barrier function after ischemia

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

Evaluation of von Willebrand Factor and von Willebrand Factor Propeptide in Models of Vascular Endothelial Cell Activation, Perturbation, and/or Injury

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