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  • br Materials and Methods br Results

    2018-11-13


    Materials and Methods
    Results
    Discussion There is an increasing awareness of the central role endothelial dysfunction plays in CV disorders. Low numbers of EPC-CFUs strongly correlate with endothelial dysfunction (Werner et al., 2007) and are associated with a high Framingham risk score for adverse CV health outcomes (Hill et al., 2003). Furthermore, circulating EPC levels predict CV events—specifically in patients with coronary artery disease, heart failure, and moclobemide (Schmidt-Lucke et al., 2005; Hill et al., 2003; Shantsila et al., 2007b). In addition, elevated levels of circulating VEGF are linked to endothelial dysfunction and HF (Chin et al., 2002; Tsai et al., 2005). In this regard, Eleuteri et al. demonstrated that elevated levels of VEGF correlated with HF disease progression (Eleuteri et al., 2011). Moreover, Wei et al. investigated circulating EPCs and VEGF levels in patients with cerebral aneurysm and found that decreased levels of circulating EPCs and increased levels of plasma VEGF were associated with chronic inflammation in the vascular walls of cerebral arteries and the development of cerebrovascular abnormalities leading to aneurysm formation and rupture (Wei et al., 2011). Thus, endothelial dysfunction is a central feature of CV disease, and may represent a powerful surrogate marker in the development of new treatments for CV disease. MSCs are adult stem cells that are prototypically found in bone marrow and have the capacity to differentiate into multiple cell types (Williams and Hare, 2011). Importantly, they stimulate the proliferation and differentiation of endogenous precursor cells and play a crucial role in maintaining stem cell niches (Williams and moclobemide Hare, 2011). In addition, MSCs secrete paracrine factors that participate in angiogenesis, cardiomyogenesis, neovascularization, stimulation of other endogenous stem cells, and regulation of the immune system (Gomes et al., 2013; Gnecchi et al., 2008). While MSCs are known to stimulate cardiac precursor cells and cell cycle activity in the heart (Hatzistergos et al., 2010), their role in stimulating other endogenous precursor populations has heretofore been unknown. Here we report that MSCs stimulated endogenous EPC activation, increasing the number and quality of functional EPCs. These findings suggest that augmentation of EPCs may represent a novel mechanism of action by which MSCs exert favorable biological effects. Over the last decade, there has been an emerging interest in the use of MSCs in CV disorders (Karantalis and Hare, in press; Telukuntla et al., 2013). Clinical trials have demonstrated a major safety profile for MSC administration, and suggested efficacy in patients with HF (Hare et al., 2012; Telukuntla et al., 2013); however, underlying mechanism(s) of action continue to be vigorously debated. Our finding that allogeneic MSC injections in patients with both ischemic and non-ischemic HF results in an improvement in endothelial function, specifically by restoring EPC function and FMD and reducing VEGF levels towards normal, offers a major new insight into the mechanisms of action of MSCs. In the study population, increased serum VEGF correlated with diminished EPC-CFUs, consistent with the idea that VEGF plays a compensatory role, a finding also reported in patients with cerebral aneurysm (Wei et al., 2011). This is also supported by the study of Vasa et al. which showed a diminished response of EPCs to VEGF in patients with CAD (Vasa et al., 2001). Moreover, Alber et al. found that a key beneficial effect of atorvastatin therapy is reducing the levels of plasma VEGF in patients with CAD (Franz Alber et al., 2002). This coincides with our study using MSCs, rather than a pharmacological intervention, to decrease pathologic VEGF and increase endothelial function. Thus our findings establish a previously unappreciated therapeutic principle whereby allogeneic MSCs can be employed to stimulate EPC bioactivity, improve arterial physiologic vasodilatory responses, and decrease unfavorable cytokine mobilization in patients with CV disease and other disorders associated with endothelial dysfunction.