Cells, biomarkers, and post-traumatic stress disorder: evidence for peripheral involvement in a central disease.

Post-traumatic stress disorder (PTSD) is a complicated CNS syndrome. Looking beyond the CNS, recent studies suggest that peripheral blood mononuclear cells could cause and/or exacerbate PTSD. This review summarizes the literature, describes associations between circulating peripheral blood cells and PTSD, proposes a novel mechanism, and analyzes several biomarkers that appear to associate with PTSD symptoms. Several experimental animal models have shown that peripheral blood mononuclear cell activity can cause hippocampal volume loss and PTSD-like symptoms. Data from these models suggest that a traumatic event and/or traumatic events can trigger peripheral cells to migrate, mediate inflammation, and decrease neurogenesis, potentially leading to CNS volume loss. Biomarkers that associate with PTSD symptoms have the potential to differentiate PTSD from traumatic brain injury, but more work needs to be done. Research examining the mechanism of how traumatic events are linked to peripheral blood mononuclear cell functions and biomarkers may offer improved diagnoses and treatments for PTSD patients.

The potential role of resistin in atherogenesis.

Resistin, an adipocyte-derived cytokine linked to insulin resistance and obesity, has recently been shown to activate endothelial cells (ECs). Using microarrays, we found that along with numerous other pro-atherosclerotic genes, resistin expression levels are elevated in the aortas of C57BL/6J apoE-/- mice; these findings led us to further explore the relation between resistin and atherosclerosis. Using TaqMan PCR and immunohistochemistry, we found that ApoE-/- mice had significantly higher resistin mRNA and protein levels in their aortas, and elevated serum resistin levels, compared to C57BL/6J wild-type mice. Incubation of murine aortic ECs with recombinant resistin increased monocyte chemoattractant protein (MCP)-1 and soluble vascular cell adhesion molecule (sVCAM)-1 protein levels in the conditioned medium. Furthermore, human carotid endarterectomy samples stained positive for resistin protein, while internal mammary artery did not show strong staining. Patients diagnosed with premature coronary artery disease (PCAD) were found to have higher serum levels of resistin than normal controls. In summary, resistin protein is present in both murine and human atherosclerotic lesions, and mRNA levels progressively increase in the aortas of mice developing atherosclerosis. Resistin induces increases in MCP-1 and sVCAM-1 expression in murine vascular endothelial cells, suggesting a possible mechanism by which resistin might contribute to atherogenesis. Finally, PCAD patients exhibited increased serum levels of resistin when compared to controls. These findings suggest a possible role of resistin in cardiovascular disease.

A new murine model of stress-induced complex atherosclerotic lesions.

The primary purpose of this investigation was to determine whether ApoE(-/-) mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE(-/-) mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability.

Interanimal variability in preexisting collaterals is a major factor determining outcome in experimental angiogenesis trials.

Despite numerous animal trials reporting that cell therapy promotes collateral flow, clinical trials have not convincingly shown benefit. Patient-related risk factors are often used to explain these discrepancies. However, during the course of our own angiogenesis studies using mice, we noted large anatomical variability in collateral vessels. The purpose of the present investigation was to define how important this factor might be in determining intervention outcomes. Hindlimb ischemia was induced in BALB/c mice by ligating the superficial femoral artery. After 24 h, animals were treated by injecting the adductor muscle with either control media or cultured mesenchymal stem cells (MSCs). Blood flow recovery was measured using laser-Doppler [laser-Doppler perfusion imaging (LDPI) ratio]. In a second experiment, mice were stratified 24 h after arterial ligation before treatment by using a simple clinical score of the ligated leg: 1, able to flex, mild discoloration; 2, no flexion, mild discoloration; 3, severe discoloration; and 4, any necrosis. Without stratification, blood flow recovery significantly increased in the MSC-treated group (P < 0.05, n = 6 MSC group, n = 7 media group). In the experiment employing stratification, all differences between the groups disappeared (n = 11 MSC group, n = 10 media group; P = 0.3). Furthermore, we found a striking inverse correlation between clinical score on day 1 and the LDPI ratio on day 28 (P < 0.0001; n = 79). Anatomical confirmation of the disparity in preexisting collaterals was found in two different mouse strains using microscopic computed tomography. In conclusion, there is substantial interanimal variability in preexisting collateral flow, and this variability can importantly influence outcome. To overcome this, either animals must be stratified before treatment, the number of animals must be increased substantially, or, preferably, both.