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Metabolite Effect on Angiogenesis: Insights from Transcriptome Analysis

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Abstract

Metabolic status of the cells is important in the expression of the angiogenic phenotype in endothelial cells. Our earlier studies demonstrated the effects of metabolites such as lactate, citrate and lipoxygenase products, on VEGFA-VEGFR2 signaling pathway. Though this link between metabolite status and molecular mechanisms of angiogenesis is becoming evident, it is not clear how it affects genome-level expression in endothelial cells, critical to angiogenesis. In the present study, computational analysis was carried out on the transcriptome data of 4 different datasets where HUVECs were exposed to low and high glucose, both in vitro and in vivo, and the expression of a key enzyme involved in glucose metabolism is altered. The differentially expressed genes belonging to both VEGFA-VEGFR2 signaling pathway, as well as several VEGF signature genes as hub genes were also identified. These findings suggest the metabolite dependence, particularly glucose dependence, of angiogenesis, involving modulation of genome-level expression of angiogenesis- functional genome. This is important in tumor angiogenesis where reprogramming of metabolism is critical.

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Abbreviations

Acronyms :

Expansion

ADP:

Adenosine Di Phosphate

AMPK:

AMP-activated protein kinase

BAM:

Compressed Binary version of Sequence Alignment Map

BC:

Betweenness Centrality

BP:

Biological Processes

CAM:

Cell Adhesion Molecule

CC:

Closeness Centrality

CNSA:

Chinese Nucleotide Sequence Archive

DAVID:

Database for Annotation, Visualization and Integrated Discovery

DC:

Degree Centrality

DEG:

Differentially Expressed Gene

EC:

Endothelial Cell

ECM:

Extra Cellular Matrix

ENA:

European Nucleotide Archive

ER:

Endoplasmic Reticulum

ERK:

Extracellular signal-Regulated Kinase

ESCC:

Esophageal Squamous Cell Carcinoma

FC:

Fold change

FDR:

False Discovery Rate

FOXO:

Forkhead Box

FPKM:

Fragments Per Kilobase per Million Reads

FTP:

File Transfer Protocol

GEO:

Gene Expression Omnibus

GO:

Gene Ontology

HDF:

Human Dermal Fibroblast

HDMEC:

Human Dermal Microvascular Endothelial Cell

HIF:

Hypoxia Inducing Factor

HISAT:

Hierarchical Indexing for Spliced Alignment of Transcripts

HUVECs:

Human Umbilical Vein Endothelial Cells

IRE1:

Inositol-Requiring Enzyme 1

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MAPK:

Mitogen- Activated Protein Kinase

MCODE:

Molecular Complex Detection

NOD:

Nucleotide-binding and Oligomerization Domain

PGC-1α:

Pparγ Coactivator 1 alpha

PI3K-Akt:

Phosphatidyl-Inositol 3-Kinase- Ak strain Transforming

PPARγ:

Peroxisome Proliferator- Activated Receptor gamma

PPI:

Protein-Protein Interaction

RIG-I:

Retinoic acid-Inducible Gene I

RNA-seq:

RNA-sequencing

SAM:

Sequence Alignment Map

STRING:

Search Tool for the Retrieval of Interacting Genes/Proteins

Wnt:

Wingless-related integration site

Gene Symbol :

Gene Name

ACAT2:

Acetyl-CoA Acetyltransferase 2

ANLN:

Anillin Actin Binding Protein

ASPM:

Assembly Factor for Spindle Microtubules

ATF6:

Activating Transcription Factor 6

C8orf33:

Chromosome 8 Open Reading Frame 33

CALR:

Calreticulin

CCL2:

C-C Motif Chemokine Ligand 2

CCNB1:

Cyclin B1

CCNB2:

Cyclin B2

CEP55:

Centrosomal Protein 55

CTSD:

Cathepsin D

CXCL1:

C-X-C Motif Chemokine Ligand 1

CXCL10:

C-X-C Motif Chemokine Ligand 10

CXCL2:

C-X-C Motif Chemokine Ligand 2

CXCL6:

C-X-C Motif Chemokine Ligand 6

CXCL8:

C-X-C Motif Chemokine Ligand 8

CXCR4:

C-X-C Motif Chemokine Receptor 4

DNAJB9:

Dnaj Heat Shock Protein Family (Hsp40) Member B9

FBXO5:

F-Box Protein 5

FGF2:

Fibroblast Growth Factor 2

HEK:

Human Epidermal Keratinocyte

HERPUD1:

Homocysteine Inducible ER Protein with Ubiquitin Like Domain 1

HIF:

Hypoxia Inducing Factor

HYOU1:

Hypoxia Up-Regulated 1

ICAM1:

Intercellular Adhesion Molecule 1

IFI6:

Interferon Alpha Inducible Protein 6

IFIH1:

Interferon Induced with Helicase C Domain 1

IFIT3:

Interferon Induced Protein with Tetratricopeptide Repeats 3

IFITM1:

Interferon Induced Transmembrane Protein 1

ISG15:

ISG15 Ubiquitin Like Modifier

LMNB1:

Lamin B1

MDA5:

Melanoma Differentiation-Associated protein 5

MRPS10:

Mitochondrial Ribosomal Protein S10

MX1:

MX Dynamin Like GTPase 1

MYCN:

MYCN Proto-Oncogene, bHLH Transcription Factor

OAS1:

2′-5′-Oligoadenylate Synthetase 1

OAS2:

2′-5′-Oligoadenylate Synthetase 2

OAS3:

2′-5′-Oligoadenylate Synthetase 3

P4HA2:

Prolyl 4-Hydroxylase Subunit Alpha 2

P4HB:

Prolyl 4-Hydroxylase Subunit Beta

PDIA6:

Protein Disulfide Isomerase Family A Member 6

PFKFB3:

6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3

PTGS1:

Prostaglandin-Endoperoxide Synthase 1

RACGAP1:

Rac GTPase Activating Protein 1

SDF2L1:

Stromal Cell Derived Factor 2 Like 1

SELE:

Selectin E

SLIT2:

Slit Guidance Ligand 2

TGFB2:

Transforming Growth Factor Beta 2

TNFAIP2:

TNF Alpha Induced Protein 2

TPX2:

TPX2 Microtubule Nucleation Factor

TYMP:

Thymidine Phosphorylase

VCAM1:

Vascular Cell Adhesion Molecule 1

VEGFA:

Vascular Endothelial Growth Factor A

VEGFR2:

Vascular Endothelial Growth Factor Receptor 2

XAF1:

XIAP Associated Factor 1

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Acknowledgements

The authors gratefully acknowledge the SIUCEB and DBT-BIF support to the Department of Computational Biology and Bioinformatics, University of Kerala, India for providing the necessary facilities and the Campus Computing Facility (CCF) at the Central Laboratory for Instrumentation and Facilitation (CLIF) at the University of Kerala for providing the HPC cluster facility to carry out this research work.

Author Contributions

Conceptualization, P.S. and P.R.S.; methodology, P.S. and P.R.S.; software, P.S.; validation, P.S. and K.R.A.; formal analysis, P.S. and P.R.S; data curation, P.S.; writing—original draft preparation, P.S. and P.R.S..; writing—review and editing, P.S., K.R.A., A.S.N., O.V.O. and P.R.S.; supervision, P.R.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Kerala State Council for Science, Technology and Environment (KSCSTE), Govt. of Kerala, by way of fellowship to K.R.A. P.R.S was supported by ISCA, Kolkata.

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  1. Department of Computational Biology and Bioinformatics, University of Kerala, Kariavattom, Thiruvananthapuram, 695581, Kerala, India

    P. Sunitha, Kesavan R. Arya, Achuthsankar S. Nair, Oommen V. Oommen & Perumana R. Sudhakaran

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Sunitha, P., Arya, K.R., Nair, A.S. et al. Metabolite Effect on Angiogenesis: Insights from Transcriptome Analysis. Cell Biochem Biophys 80, 519–536 (2022). https://doi.org/10.1007/s12013-022-01078-0

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