scholarly journals Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells

Angiogenesis ◽  
2020 ◽  
Author(s):  
Carlotta Tacconi ◽  
Yuliang He ◽  
Luca Ducoli ◽  
Michael Detmar
Keyword(s):  
Dna Methylation ◽  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Transcriptional Level ◽  
Vascular Endothelial ◽  
Lineage Specificity ◽  
Endothelial Lineage ◽  
Lineage Markers ◽  
Developmental Features

Abstract Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the transcriptomic landscapes, histone composition (H3K4me3 and H3K27me3) and DNA methylomes of cultured matched human primary dermal lymphatic and blood vascular ECs. Our findings reveal that blood vascular lineage genes manifest a more ‘repressed’ histone composition in lymphatic ECs, whereas DNA methylation at promoters is less linked to the differential transcriptomes of lymphatic versus blood vascular ECs. Meta-analyses identified two transcriptional regulators, BCL6 and MEF2C, which potentially govern endothelial lineage specificity. Notably, the blood vascular endothelial lineage markers CD34, ESAM and FLT1 and the lymphatic endothelial lineage markers PROX1, PDPN and FLT4 exhibited highly differential epigenetic profiles and responded in distinct manners to epigenetic drug treatments. The perturbation of histone and DNA methylation selectively promoted the expression of blood vascular endothelial markers in lymphatic endothelial cells, but not vice versa. Overall, our study reveals that the fine regulation of lymphatic and blood vascular endothelial transcriptomes is maintained via several epigenetic mechanisms, which are crucial to the maintenance of endothelial cell identity.

Novel control of cAMP-regulated transcription in vascular endothelial cells

2012 ◽  
Vol 40 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Gillian R. Milne ◽  
Timothy M. Palmer ◽  
Stephen J. Yarwood
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Vascular Endothelial Cells ◽  
Inflammatory Diseases ◽  
Circulatory System ◽  
Vascular Endothelial ◽  
Protective Mechanisms ◽  
Enhancer Binding Protein ◽  
Developed World

Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel ‘protective’ mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease.

scholarly journals Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

2003 ◽  
Vol 83 (1) ◽  
pp. 59-115 ◽  
Author(s):  
Dirk L. Brutsaert
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathways ◽  
Cardiac Failure ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Endothelial Activation ◽  
Cardiac Metabolism ◽  
Vascular Endothelial ◽  
Adult Heart ◽  
Contractile Performance

Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I2, and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.

scholarly journals Endothelial specific YY1 deletion restricts tumor angiogenesis and tumor growth

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Huan Liu ◽  
Yikai Qiu ◽  
Xiuying Pei ◽  
Ramamurthy Chitteti ◽  
Rebbeca Steiner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Vital Role ◽  
Vascular Endothelial

AbstractAngiogenesis is a physiological process for the formation of new blood vessels from the pre-existing vessels and it has a vital role in the survival and growth of neoplasms. During tumor angiogenesis, the activation of the gene transcriptions in vascular endothelial cells (ECs) plays an essential role in the promotion of EC proliferation, migration, and vascular network development. However, the molecular mechanisms underlying transcriptional regulation of EC and tumor angiogenesis remains to be fully elucidated. Here we report that the transcription factor Yin Yang 1 (YY1) in ECs is critically involved in tumor angiogenesis. First, we utilized a tamoxifen-inducible EC-specific YY1 deficient mouse model and showed that YY1 deletion in ECs inhibited the tumor growth and tumor angiogenesis. Using the in vivo matrigel plug assay, we then found that EC-specific YY1 ablation inhibited growth factor-induced angiogenesis. Furthermore, vascular endothelial growth factor (VEGF)-induced EC migration was diminished in YY1-depleted human umbilical vein endothelial cells (HUVECs). Finally, a rescue experiment revealed that YY1-regulated BMP6 expression in ECs was involved in EC migration. Collectively, our results demonstrate that endothelial YY1 has a crucial role in tumor angiogenesis and suggest that targeting endothelial YY1 could be a potential therapeutic strategy for cancer treatment.

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