The in vivo endothelial cell translatome is highly heterogeneous across vascular beds

Cleuren, Audrey C. A.; Ent, Martijn A. van der; Jiang, Hui; Hunker, Kristina L.; Yee, Andrew; Siemieniak, David; Molema, Grietje; Aird, William C.; Ganesh, Santhi K.; Ginsburg, David

doi:10.1073/pnas.1912409116

Cited by 109 publications

(128 citation statements)

References 73 publications

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“…Of note, endothelial cells show organotypic heterogeneity with highly specific functions, e.g. formation of the blood-brain-barrier or the renal glomerular filtration barrier, which is reflected by their transcriptome and translatome [4][5][6][7] . Cardiac endothelial cells take specific functions in energy metabolism and substrate supply 8 .…”

mentioning

confidence: 99%

Gene expression in immortalized versus primary isolated cardiac endothelial cells

Deng

Pollmeier

Zhou

et al. 2020

Sci Rep

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Endothelial cells take pivotal roles in the heart and the vascular system and their differentiation, subspecification and function is determined by gene expression. A stable, in vitro cardiac endothelial cell line could provide high cell numbers as needed for many epigenetic analyses and facilitate the understanding of molecular mechanisms involved in endothelial cell biology. To test their suitability for transcriptomic or epigenetic studies, we compared the transcriptome of cultured immortalized mouse cardiac endothelial cells (MCEC) to primary cardiac endothelial cells (pEC). Whole transcriptome comparison of MCEC and pEC showed a correlation of 0.75-0.77. Interestingly, correlation of gene expression declined in endothelial cell-typical genes. In MCEC, we found a broad downregulation of genes that are highly expressed in pEC, including well-described markers of endothelial cell differentiation. Accordingly, systematic analysis revealed a downregulation of genes associated with typical endothelial cell functions in MCEC, while genes related to mitotic cell cycle were upregulated when compared to pEC. In conclusion, the findings from this study suggest that primary cardiac endothelial cells should preferably be used for genome-wide transcriptome or epigenome studies. The suitability of in vitro cell lines for experiments investigating single genes or signaling pathways should be carefully validated before use.

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mentioning

confidence: 99%

Gene expression in immortalized versus primary isolated cardiac endothelial cells

Deng

Pollmeier

Zhou

et al. 2020

Sci Rep

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“…Molecular and functional differences exist between endothelial cells of various blood vessels and vascular beds, and this diversity may arise due to microenvironmental factors. In support, transplanted endothelial cells gain structural phenotypes and gene expression patterns associated with new host tissue 66,67 and endothelial cells with distinct molecular signatures regress towards a common phenotype upon in vitro expansion 39,68 . In obesity, differences in the local environment may arise from variation in lipid accumulation among endothelial cells 69 .…”

Section: Discussionmentioning

confidence: 96%

“…This arrangement allows the endothelium to detect and process multiple stimuli in parallel and to generate stimulusspecific responses [30][31][32][33] . These findings, together with studies that describe molecular [34][35][36][37][38][39][40][41] and functional heterogeneity 40,42 in endothelial cells across vascular beds, and within single vessel segments, raise the possibility that dysfunctional vascular responses could arise from altered endothelial cell heterogeneity and disrupted network dynamics. Indeed, altered mulitcellular network behavior underlies disease development in a variety of physiological systems.…”

Section: Introductionmentioning

confidence: 99%

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

Wilson

Zhang

Lee

et al. 2020

Preprint

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Rationale: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations giving rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that, rather than being a population of uniformly responding cells, neighboring endothelial cells are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function.Objective: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contributes to impaired vascular reactivity in obesity. Methods and Results:To study obesity-related vascular function without the complications associated with diabetes, we induced a state of prediabetic obesity in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and network-level calcium responses. Obesity did not alter the slope of this relationship, but impaired network-level endothelial calcium responses. The network itself was comprised of structural and functional components. The structural component, a hexagonal lattice network of endothelial cells, was unchanged in obesity. The functional network contained subpopulations of clustered agonist-sensing cells from which signals were communicate through the network. In obesity there were fewer but larger clusters of agonist-sensing cells and communication path lengths between clusters was increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Specialized subpopulations of endothelial cells had increased agonist sensitivity. These agonistresponsive cells were spatially clustered in a non-random manner and drove network level calcium responses. Communication between adjacent cells was unaltered in obesity, but there was a decrease in the size of the agonist-sensitive cell population and an increase in the clustering of agonist-responsive cells Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular function. Altered cell heterogeneity and arrangement in obesity decrease endothelial function and provide a novel framework for understanding compromised endothelial function in cardiovascular disease.

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“…Molecular and functional diversity in endothelial cells may arise from local microenvironmental factors. In support, transplanted endothelial cells gain structural phenotypes and gene expression patterns associated with new host tissue [67,91] and endothelial cells with distinct molecular signatures regress towards a common phenotype upon in vitro expansion [39,92]. In obesity, differences in the local environment may also arise from variation in lipid accumulation among endothelial cells [93].…”

Section: Discussionmentioning

confidence: 99%

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

et al. 2020

View full text Add to dashboard Cite

Background: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. Purpose: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. Methods and results: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. Conclusions: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.

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The in vivo endothelial cell translatome is highly heterogeneous across vascular beds

Cited by 109 publications

References 73 publications

Gene expression in immortalized versus primary isolated cardiac endothelial cells

Gene expression in immortalized versus primary isolated cardiac endothelial cells

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity

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