Biomarkers of Endothelial Cell Activation Serve as Potential Surrogate Markers for Drug-induced Vascular Injury
Open Access
- 17 August 2010
- journal article
- review article
- Published by SAGE Publications in Toxicologic Pathology
- Vol. 38 (6), 856-871
- https://doi.org/10.1177/0192623310378866
Abstract
Drug-induced vascular injury (DIVI) is a nonclinical finding that often confounds the toxicological evaluation of investigational drugs, but there is an absence of qualified biomarkers that can be used to detect and monitor its appearance in animals and patients during drug development and clinical use. It is well known that endothelial cell (EC) activation plays a key role in the expression and evolution of DIVI, and the various immunological and inflammatory factors involved in its expression may serve as potential biomarker candidates. Activated ECs change their morphology and gene expression, generating endothelial adhesion molecules, pro-coagulant molecules, cytokines, chemokines, vasodilators, nitric oxide, and acute-phase reactants. This review provides a brief historical background of EC activation and the search for biomarkers of early EC activation for monitoring DIVI. At present, no biomarkers of EC activation have been qualified to predict DIVI in the nonclinical or clinical context, and a robust pathologic foundation for their use is still lacking. We propose three categories of EC activation biomarkers: recommended surrogate markers, potentially useful markers, and emerging candidate markers. This review alerts pharmaceutical companies, research institutions, and regulatory agencies to the continuing need for reliable biomarkers of EC activation in drug development.Keywords
This publication has 99 references indexed in Scilit:
- Immunomagnetic isolation of canine circulating endothelial and endothelial progenitor cellsVeterinary Clinical Pathology, 2009
- Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A, and PECAM-1Blood, 2009
- Lowering Caveolin-1 Expression in Human Vascular Endothelial Cells Inhibits Signal Transduction in Response to Shear StressInternational Journal of Cell Biology, 2008
- Caveolae and transcytosis in endothelial cells: role in atherosclerosisCell and tissue research, 2008
- Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout miceThe Journal of Experimental Medicine, 2007
- Junctional adhesion molecule‐A regulates cell migration and resistance to shear stressJournal of Cellular Physiology, 2006
- A20 Protects From CD40-CD40 Ligand-Mediated Endothelial Cell Activation and ApoptosisCirculation, 2003
- Caveolin, Caveolae, and Endothelial Cell FunctionArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- Endothelial Apoptosis Induced by Oxidative Stress Through Activation of NF-κBHypertension, 2001
- Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cellsBiochemical and Biophysical Research Communications, 1992