Genetic control of erythropoiesis.
Curr Opin Hematol. 2017 Feb 15;:
Authors: Tumburu L, Thein SL
PURPOSE OF REVIEW: The discovery of several genetic variants associated with erythroid traits and subsequent elucidation of their functional mechanisms are exemplars of the power of the new genetic and genomic technology. The present review highlights findings from recent genetic studies related to the control of erythropoiesis and dyserythropoiesis, and fetal hemoglobin, an erythroid-related trait.
RECENT FINDINGS: Identification of the genetic modulators of erythropoiesis involved two approaches: genome-wide association studies (GWASs) using single nucleotide polymorphism (SNP) arrays that revealed the common genetic variants associated with erythroid phenotypes (hemoglobin, red cell count, MCV, MCH) and fetal hemoglobin; and massive parallel sequencing such as whole genome sequencing (WGS) and whole exome sequencing (WES) that led to the discovery of the rarer variants (GFI1B, SBDS, RPS19, PKLR, EPO, EPOR, KLF1, GATA1). Functional and genomic studies aided by computational approaches and gene editing technology refined the regions encompassing the putative causative SNPs and confirmed their regulatory role at different stages of erythropoiesis.
SUMMARY: Five meta-analysis of GWASs identified 17 genetic loci associated with erythroid phenotypes, which are potential regulators of erythropoiesis. Some of these loci showed pleiotropy associated with multiple erythroid traits, suggesting undiscovered molecular mechanisms and challenges underlying erythroid biology. Other sequencing strategies (WGS and WES) further elucidated the role of rare variants in dyserythropoiesis. Integration of common and rare variant studies with functional assays involving latest genome-editing technologies will significantly improve our understanding of the genetics underlying erythropoiesis and erythroid disorders.
PMID: 28212192 [PubMed - as supplied by publisher]
Endothelial cell metabolism: an update anno 2017.
Curr Opin Hematol. 2017 Feb 15;:
Authors: Teuwen LA, Draoui N, Dubois C, Carmeliet P
PURPOSE OF REVIEW: Endothelial cell metabolism has recently emerged as an important coregulator of angiogenesis and is therefore a promising new target in various angiogenesis-associated illnesses, like cancer. In this review, we discuss recent insights in endothelial cell metabolism in both physiological and pathological conditions and discuss possible translational implications.
RECENT FINDINGS: Two metabolic pathways that determine the performance of endothelial cells are glycolysis and fatty acid oxidation (FAO). Glycolysis is essential as endothelial cells primarily rely on this pathway for ATP production. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a key regulator of glycolysis in endothelial cells. As endothelial cells increase glycolysis even further during angiogenesis, PFKFB3 also controls vessel sprouting and promotes endothelial cell migration. Moreover, in tumors, additional PFKFB3 upregulation leads to a more immature and dysfunctional vasculature. PFKFB3 blockade therefore results in tumor vessel normalization, with beneficial therapeutic effects on reduced metastasis and improved chemotherapy. Also, FAO stimulates endothelial cell proliferation through affecting DNA synthesis, and is critical for lymphangiogenesis, in part through epigenetic changes in histone acetylation. As FAO is controlled by carnitine palmitoyltransferase 1a, inhibition of this key enzyme decreases pathological angiogenesis.
SUMMARY: Both PFKFB3 and carnitine palmitoyltransferase 1a are key metabolic regulators of vessel sprouting and promising new therapeutic targets in diseases associated with pathological angiogenesis.
PMID: 28212191 [PubMed - as supplied by publisher]
Endothelial cell disease: emerging knowledge from cerebral cavernous malformations.
Curr Opin Hematol. 2017 Feb 16;:
Authors: Lampugnani MG, Malinverno M, Dejana E
PURPOSE OF REVIEW: Endothelial cells dysfunctions are crucial determinants of several human diseases. We review here the most recent reports on endothelial cell defects in cerebral cavernous malformations (CCMs), particularly focusing on adherens junctions. CCM is a vascular disease that affects specifically the venous microvessels of the central nervous system and which is caused by loss-of-function mutation in any one of the three CCM genes (CCM1, 2 or 3) in endothelial cells. The phenotypic result of these mutations are focal vascular malformations that are permeable and fragile causing neurological symptoms and occasionally haemorrhagic stroke.
RECENT FINDINGS: CCM is still an incurable disease, as no pharmacological treatment is available, besides surgery. The definition of the molecular alterations ensuing loss of function mutation of CCM genes is contributing to orientate the testing of targeted pharmacological tools.Several signalling pathways are altered in the three genotypes in a similar way and concur in the acquisition of mesenchymal markers in endothelial cells. However, also genotype-specific defects are reported, in particular for the CCM1 and CCM3 mutation.
SUMMARY: Besides the specific CCM disease, the characterization of endothelial alterations in CCM has the potentiality to shed light on basic molecular regulations as the acquisition and maintenance of organ and vascular site specificity of endothelial cells.
PMID: 28212190 [PubMed - as supplied by publisher]
Wnt signaling in the vessel wall.
Curr Opin Hematol. 2017 Feb 16;:
Authors: Badimon L, Borrell-Pages M
PURPOSE OF REVIEW: Wnt signaling plays a crucial role during embryogenesis. In an adult, Wnt is mainly associated to cellular proliferation and differentiation mechanisms. Recent data suggest that Wnt signaling is involved in the pathophysiology of atherosclerosis. However, the roles of Wnt signaling pathways in the vessel wall are poorly understood. This review outlines recent discoveries in understanding the role of Wnt pathways in healthy and atherosclerotic vessels.
RECENT FINDINGS: In the last years, the involvement of both canonical and noncanonical Wnt pathways in the development of atherosclerotic lesions has been recognized. Indeed, several Wnt pathway components have been shown to participate in the early, intermediate, and late stages of atherosclerosis development. Specifically, the role of the Wnt coreceptors low-density lipoprotein receptor-related protein 5 and low-density lipoprotein receptor-related protein 6 seems to be crucial for atherosclerotic plaque progression.
SUMMARY: Many of the clinical trials developed in the last decade to reduce atherosclerosis and cardiovascular diseases have been futile or have failed possibly because of a poor understanding of new mechanisms that lead to diseases. The understanding of the signaling pathways involved in human atherosclerosis development should help in the development of future therapies.
PMID: 28212189 [PubMed - as supplied by publisher]