Vascular Imaging of Matrix Metalloproteinase Activity as an Informative Preclinical Biomarker of Drug-induced Vascular Injury

Abstract

Lack of biomarkers specific to and either predictive or diagnostic of drug-induced vascular injury (DIVI) continues to be a major obstacle during drug development. Biomarkers derived from physiologic responses to vessel injury, such as inflammation and vascular remodeling, could make good candidates; however, they characteristically lack specificity for vasculature. We evaluated whether vascular remodeling-associated protease activity, as well as changes to vessel permeability resulting from DIVI, could be visualized ex vivo in affected vessels, thereby allowing for visual monitoring of the pathology to address specificity. We found that visualization of matrix metalloproteinase activation accompanied by increased vascular leakage in the mesentery of rats treated with agents known to induce vascular injury correlated well with incidence and severity of histopathological findings and associated inflammation as well as with circulating levels of tissue inhibitors of metalloproteinase 1 and neutrophil gelatinase-associated lipocalin. The weight of evidence approach reported here shows promise as a composite DIVI preclinical tool by means of complementing noninvasive monitoring of circulating biomarkers of inflammation with direct imaging of affected vasculature and thus lending specificity to its interpretation. These findings are supportive of a potential strategy that relies on translational imaging tools in conjunction with circulating biomarker data for high-specificity monitoring of VI both preclinically and clinically.

Angiogenesis: A Cellular Response to Traumatic Injury

“…MMP-9 has been shown to result in elevated CXCL12 levels, and reciprocally CXCL12 increased MMP-9 concentration in bone marrow cells (50). Increases in circulating MMP-9 concentration have been observed following traumatic insult (51)(52)(53). This is quite similar to studies demonstrating the increase of MMP-9 in patients with sepsis (54)(55)(56).…”

Detection of fenoldopam-induced arteritis in rats using ex vivo / in vivo MRI

“…FM was administered subcutaneously to each rat (6 weeks of age at the start of administration) once daily for 2 days at dose of 100 mg/kg/day in saline (5 ml/kg). The dose was selected based on earlier reports [2] , [6] . As vehicle control, saline only was administered to animals in the same way described above.…”