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Eelen G.,Vesalius Research Center | De Zeeuw P.,Vesalius Research Center | Simons M.,Yale Cardiovascular Research Center | Simons M.,Yale University | Carmeliet P.,Vesalius Research Center
Circulation Research | Year: 2015

Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg, vascular endothelial growth factor) and other signals (eg, Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or affects the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored EC metabolism-centric therapeutic avenues are discussed. © 2015 American Heart Association, Inc. Source

Faber J.E.,University of North Carolina at Chapel Hill | Chilian W.M.,Northeast Ohio Medical University | Deindl E.,Ludwig Maximilians University of Munich | Van Royen N.,VU University Amsterdam | Simons M.,Yale Cardiovascular Research Center
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

It is well known that the protective capacity of the collateral circulation falls short in many individuals with ischemic disease of the heart, brain, and lower extremities. In the past 15 years, opportunities created by molecular and genetic tools, together with disappointing outcomes in many angiogenic trials, have led to a significant increase in the number of studies that focus on: understanding the basic biology of the collateral circulation; identifying the mechanisms that limit the collateral circulation's capacity in many individuals; devising methods to measure collateral extent, which has been found to vary widely among individuals; and developing treatments to increase collateral blood flow in obstructive disease. Unfortunately, accompanying this increase in reports has been a proliferation of vague terms used to describe the disposition and behavior of this unique circulation, as well as the increasing misuse of well-ensconced ones by new (and old) students of collateral circulation. With this in mind, we provide a brief glossary of readily understandable terms to denote the formation, adaptive growth, and maladaptive rarefaction of collateral circulation. We also propose terminology for several newly discovered processes that occur in the collateral circulation. Finally, we include terms used to describe vessels that are sometimes confused with collaterals, as well as terms describing processes active in the general arterial-venous circulation when ischemic conditions engage the collateral circulation. We hope this brief review will help unify the terminology used in collateral research. © 2014 American Heart Association, Inc. Source

Simons M.,Yale Cardiovascular Research Center
Physiology | Year: 2012

Vascular endothelial growth factors (VEGF) and their receptors play a central role in the development of cardiovascular system and in vasculature-related processes in the adult organism. Given the critical role of this signaling cascade, intricate control systems have evolved to regulate its function. A new layer of added complexity has been the demonstration of the importance of endocytosis and intracellular trafficking of VEGF receptors in the regulation of VEGF signaling. In this review, we consider an evolving link between VEGF receptor endocytosis, trafficking, and signaling and their biological function. © 2012 Int. Union Physiol. Sci./Am. Physiol. Soc. Source

Simons M.,Yale Cardiovascular Research Center | VanHook A.M.,American Association for the Advancement of Science
Science Signaling | Year: 2014

This Podcast features an interview with Micael Simons, senior author of a Research Article that appears in the 23 September 2014 issue of Science Signaling, about how FGF signaling inhibits TGF-ß signaling to prevent endothelial-to-mesenchymal transitions in blood vessels. An important part of vascular homeostasis is maintaining the sheet of endothelial cells that line blood vessels. Endothelial cells are flattened, polarized cells that are tightly connected to one another to form a continuous sheet. Under certain conditions, endothelial cells can undergo an endothelial-to-mesenchymal transition (EndMT), in which the cells lose their polarity and become less tightly associated with one another. This change in morphology and cell biology impedes the normal function of blood vessels. Transforming growth factor-ß (TGF-ß) signaling can induce EndMT, and signaling through the fibroblast growth factor (FGF) pathway prevents EndMT under normal conditions. Chen et al. found that FGF signaling through the receptor FGFR1 suppressed EndMT by inducing the expression of a microRNA that decreases the abundance of a TGF-ß receptor, thus repressing TGF-ß signaling. © 2014 American Association for the Advancement of Science. Source

Nicoli S.,University of Massachusetts Medical School | Nicoli S.,Yale Cardiovascular Research Center | Knyphausen C.-P.,University of Massachusetts Medical School | Knyphausen C.-P.,University of Munster | And 3 more authors.
Developmental Cell | Year: 2012

Angiogenesis requires coordination of distinct cell behaviors between tip and stalk cells. Although thisprocess is governed by regulatory interactions between the vascular endothelial growth factor (Vegf) and Notch signaling pathways, little is known about the potential role of microRNAs. Through deep sequencing and functional screening in zebrafish, we find that miR-221 is essential for angiogenesis. miR-221 knockdown phenocopied defects associated with loss of the tip cell-expressed Flt4 receptor. Furthermore, miR-221 was required for tip cell proliferation and migration, as well as tip cell potential in mosaic blood vessels. miR-221 knockdown also prevented " hyper-angiogenesis" defects associated with Notch deficiency and miR-221 expression was inhibited by Notch signaling. Finally, miR-221 promoted tip cell behavior through repression of two targets: cyclin dependent kinase inhibitor 1b (cdkn1b) and. phosphoinositide-3-kinase regulatory subunit 1 (pik3r1). These results identify miR-221 as an important regulatory node through which tip cell migration and proliferation are controlled during angiogenesis. Angiogenesis requires coordination of distinct cell behaviors between sprouting tip cells and the stalk cells connected to the patent circulatory system. Nicoli etal. identify a microRNA, miR-221, that is required for tip cell migration and proliferation through the repression of targets involved in PI3K signaling and cell cycle inhibition. © 2012 Elsevier Inc. Source

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