Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis

Blood vessel expansion is driven by sprouting angiogenesis of endothelial cells, and is essential for development, wound healing and disease. Membrane-localized vascular endothelial growth factor receptor-1 (mVEGFR1) is an endothelial cell-intrinsic decoy receptor that negatively modulates blood vessel morphogenesis. Here we show that dynamic regulation of mVEGFR1 stability and turnover in blood vessels impacts angiogenesis. mVEGFR1 is highly stable and constitutively internalizes from the plasma membrane. Post-translational palmitoylation of mVEGFR1 is a binary stabilization switch, and ligand engagement leads to depalmitoylation and lysosomal degradation. Trafficking of palmitoylation enzymes via Rab27a regulates mVEGFR1 stability, as reduced levels of Rab27a impaired palmitoylation of mVEGFR1, decreased its stability, and elevated blood vessel sprouting and in vivo angiogenesis. These findings identify a regulatory axis affecting blood vessel morphogenesis that highlights exquisite post-translational regulation of mVEGFR1 in its role as a molecular rheostat

Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6

Functional blood vessel growth depends on generation of distinct but coordinated responses from endothelial cells. Bone morphogenetic proteins (BMP), part of the TGFβ superfamily, bind receptors to induce phosphorylation and nuclear translocation of SMAD transcription factors (R-SMAD1/5/8) and regulate vessel growth. However, SMAD1/5/8 signalling results in both pro- and anti-angiogenic outputs, highlighting a poor understanding of the complexities of BMP signalling in the vasculature. Here we show that BMP6 and BMP2 ligands are pro-angiogenic in vitro and in vivo, and that lateral vessel branching requires threshold levels of R-SMAD phosphorylation. Endothelial cell responsiveness to these pro-angiogenic BMP ligands is regulated by Notch status and Notch sets responsiveness by regulating a cell-intrinsic BMP inhibitor, SMAD6, which affects BMP responses upstream of target gene expression. Thus, we reveal a paradigm for Notch-dependent regulation of angiogenesis: Notch regulates SMAD6 expression to affect BMP responsiveness of endothelial cells and new vessel branch formation

Extent, nature and consequences of performing outside scope of training in global health

Background Globalization has made it possible for global health professionals and trainees to participate in short-term training and professional experiences in a variety of clinical- and non-clinical activities across borders. Consequently, greater numbers of healthcare professionals and trainees from high-income countries (HICs) are working or volunteering abroad and participating in short-term experiences in low- and middle-income countries (LMICs). How effective these activities are in advancing global health and in addressing the crisis of human resources for health remains controversial. What is known, however, is that during these short-term experiences in global health (STEGH), health professionals and those in training often face substantive ethical challenges. A common dilemma described is that of acting outside of one’s scope of training. However, the frequency, nature, circumstances, and consequences of performing outside scope of training (POST) have not been well-explored or quantified. Methods The authors conducted an online survey of HIC health professionals and trainees working or volunteering in LMICs about their experiences with POST, within the last 5 years. Results A total of 223 survey responses were included in the final analysis. Half (49%) of respondents reported having been asked to perform outside their scope of training; of these, 61% reported POST. Trainees were nearly twice as likely as licensed professionals to report POST. Common reasons cited for POST were a mismatch of skills with host expectations, suboptimal supervision at host sites, inadequate preparation to decline POST, a perceived lack of alternative options and emergency situations. Many of the respondents who reported POST expressed moral distress that persisted over time. Conclusions Given that POST is ethically problematic and legally impermissible, the high rates of being asked, and deciding to do so, were notable. Based on these findings, the authors suggest that additional efforts are needed to reduce the incidence of POST during STEGH, including pre-departure training to navigate dilemmas concerning POST, clear communication regarding expectations, and greater attention to the moral distress experienced by those contending with POST