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The MADS box transcription factor MEF2C has been detected by us to be upregulated by the angiogenic factors VEGF-A and bFGF in endothelial cells. We have here investigated its potential role for angiogenesis. MEF2C was surprisingly found to strongly inhibit angiogenic sprouting, whereas a dominant negative mutant rather induced sprouting. The factor mainly affected migratory processes of endothelial cells, but not proliferation. In gene profiling experiments we delineated the alpha-2-macroglobulin gene to be highly upregulated by MEF2C. Further data confirmed that MEF2C in endothelial cells indeed induces alpha-2-macroglobulin mRNA as well as the secretion of alpha-2-macroglobulin and that conditioned supernatants of cells overexpressing MEF2C inhibit sprouting. Alpha-2-macroglobulin mediates, at least to a large extent, the inhibitory effects of MEF2C as is shown by knockdown of alpha-2-macroglobulin mRNA by lentiviral shRNA expression which reduces the inhibitory effect. However, under hypoxic conditions the VEGF-A/bFGF-mediated upregulation of MEF2C is reduced and the production of alpha-2-macroglobulin largely abolished. Taken together, this suggests that the MEF2C/alpha-2-macroglobulin axis functions in endothelial cells as a negative feed-back mechanism that adapts sprouting activity to the oxygen concentration thus diminishing inappropriate and excess angiogenesis.

Endothelial colony forming cells (ECFC) or late blood outgrowth endothelial cells (BOEC) have been proposed to contribute to neovascularization in humans. Exploring genes characteristic for the progenitor status of ECFC we have identified the forkhead box transcription factor FOXF1 to be selectively expressed in ECFC compared to mature endothelial cells isolated from the vessel wall. Analyzing the role of FOXF1 by gain- and loss-of-function studies we detected a strong impact of FOXF1 expression on the particularly high sprouting capabilities of endothelial progenitors. This apparently relates to the regulation of expression of several surface receptors. First, FOXF1 overexpression specifically induces the expression of Notch2 receptors and induces sprouting. Vice versa, knock-down of FOXF1 and Notch2 reduces sprouting. In addition, FOXF1 augments the expression of VEGF receptor-2 and of the arterial marker ephrin B2, whereas it downmodulates the venous marker EphB4. In line with these findings on human endothelial progenitors, we further show that knockdown of FOXF1 in the zebrafish model alters, during embryonic development, the regular formation of vasculature by sprouting. Hence, these findings support a crucial role of FOXF1 for endothelial progenitors and connected vascular sprouting as it may be relevant for tissue neovascularization. It further implicates Notch2, VEGF receptor-2, and ephrin B2 as downstream mediators of FOXF1 functions.

Background Outcome after ST‐elevation myocardial infarction (STEMI) can be most reliably estimated by cardiac magnetic resonance (CMR) imaging. However, CMR is expensive, laborious, and has only limited availability. In comparison, transthoracic echocardiography (TTE) is widely available and cost‐efficient. Hypothesis TTE strain parameters can be used as surrogate markers for CMR‐measured parameters after STEMI. Methods TTE strain analysis was performed of patients included in a controlled, prospective STEMI trial (NCT01777750) 4 ± 2 days after the event. Longitudinal peak strain (LPS), post‐systolic shortening, early systolic lengthening, early systolic lengthening time, and time to peak shortening were measured, and index parameters were computed. Global longitudinal strain (GLS) and ejection fraction (EF) were compiled. Parameters were correlated with CMR‐measured variables 4 ± 2 days after STEMI. Results In 70 STEMI patients, high quality CMR and TTE data were available. Highest correlation with CMR‐measured infarct size was observed with GLS (r = 0.577, p < 0.0001), LPS (r = 0.571, p < 0.0001), and EF (r = −0.533, p < 0.0001). Highest correlation with CMR‐measured area at risk was observed with GLS (r = 0.666, p < 0.0001), LPS (0.661, p < 0.0001) and early systolic lengthening index (r = 0.540, p < 0.0001). Receiver operating characteristics for the detection of large infarcts (quartile with highest infarct size) showed the highest area under the curve for LPS, GLS, EF, and myocardial dysfunction index. Multiple linear regression displayed the best association between GLS and infarct size. Conclusion Exploratory strain parameters significantly correlate with CMR‐measured area at risk and infarct size and are of potential interest as endpoint variables in clinical trials.