title: Optical imaging biomarkers of drug-induced vascular injury.
abstract: Drug-induced vascular injury (DIVI), defined as arterial medial degeneration/necrosis usually associated with perivascular inflammation, is frequently observed in the mesenteric arteries of rats but the relevance to humans remains a hurdle for drug development. Here, we describe the evaluation of commercially available optical imaging biomarkers using a rat DIVI model. Male Sprague Dawley rats were administered 10 mg/kg/day of a proprietary soluble guanylate cyclase activator (sGCa). Optical agents, AngioSense for the detection of vessel permeability, MMPSense for the detection of activated matrix metalloproteinases (MMPs), and IntegriSense for the detection of αvβ3 integrin, were injected via tail vein 24 hours before fluorescence (FL) ex vivo imaging. Imaging found a statistically significant difference in FL from all optical agents between treated and vehicle groups (p < .05). Mesenteric arteries were further analyzed by histopathology, flow cytometry, and immunohistochemistry. Histopathology confirmed perivascular inflammation and/or arterial medial degeneration in the sGCa-treated animals. Flow cytometry of digested arteries revealed myeloid cells as a main source of MMPSense signal. Immunohistochemical analysis further identified elevated MMP-9 expression within arterial walls and surrounding tissue of treated animals. Together, these data demonstrate that MMPSense and AngioSense are sensitive optical imaging biomarkers for the quantification of DIVI in rat mesenteric arteries.
authors.forename: Shu-An
authors.initials: SA
authors.lastname: Lin
authors.forename: Donna L
authors.initials: DL
authors.lastname: Suresch
authors.forename: Brett
authors.initials: B
authors.lastname: Connolly
authors.forename: Gebre
authors.initials: G
authors.lastname: Mesfin
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Gonzalez
authors.forename: Manishkumar R
authors.initials: MR
authors.lastname: Patel
authors.forename: Diane
authors.initials: D
authors.lastname: Shevell
authors.forename: Timothy
authors.initials: T
authors.lastname: Johnson
authors.forename: Bohumil
authors.initials: B
authors.lastname: Bednar
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000737:chemistry*; D005434:Flow Cytometry; D051604:Guanylate Cyclase-Activating Proteins / Q000737:chemistry; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008638:Mesenteric Arteries / Q000473:pathology; D008856:Microscopy, Fluorescence; D061848:Optical Imaging; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051604:Guanylate Cyclase-Activating Proteins; D039302:Integrin alphaVbeta3; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat