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Establishing a Link Between Endothelial Cell Metabolism and Vascular Behaviour in a Type 1 Diabetes Mouse Model

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Title: Establishing a Link Between Endothelial Cell Metabolism and Vascular Behaviour in a Type 1 Diabetes Mouse Model
Authors: Silva, C, Sampaio-Pinto, V, Andrade, S, Rodrigues, I, Costa, R, Guerreiro, SG, Carvalho, E, Pinto-do-Ó, P, Nascimento, DS, Soares, R
Contributors: Instituto de Investigação e Inovação em Saúde
Source: Cell Physiol Biochem
Cellular Physiology and Biochemistry, Vol 52, Iss 3, Pp 503-516 (2019)
Publisher Information: Cell Physiol Biochem Press GmbH and Co KG, 2019.
Publication Year: 2019
Subject Terms: Male, 0301 basic medicine, Physiology, Connective Tissue Growth Factor / analysis, Kidney / cytology, Microvessels / pathology, Carbohydrate and lipid metabolism, Kidney, Biochemistry, Mice, Transforming Growth Factor beta, Transforming Growth Factor beta / metabolism, QP1-981, Macrovascular complications, Vascular Endothelial Growth Factor Receptor-2 / genetics, Tissue Inhibitor of Metalloproteinase-2 / genetics, 0303 health sciences, Neovascularization, Pathologic, Receptors, Notch, Endothelial Cells / metabolism, Genomics, Platelet Endothelial Cell Adhesion Molecule-1 / metabolism, 3. Good health, Platelet Endothelial Cell Adhesion Molecule-1, Diabetes Mellitus, Experimental / pathology, Cell sorting, Diabetes Mellitus, Experimental / chemically induced, Receptors, Notch / metabolism, Diabetes Mellitus, Experimental / metabolism, Endothelial Cells / cytology, Kidney / metabolism, Microvessels / physiology, Myocardium / metabolism, Heart Ventricles, Micro and macrovascular complications, QD415-436, Transforming Growth Factor beta / genetics, Article, Diabetes Mellitus, Experimental, Connective Tissue Growth Factor / metabolism, 03 medical and health sciences, Vascular Endothelial Growth Factor Receptor-2 / metabolism, Heart Ventricles / metabolism, Tissue Inhibitor of Metalloproteinase-2 / metabolism, Animals, Tissue Inhibitor of Metalloproteinase-2, Myocardium, Micro, Connective Tissue Growth Factor, Endothelial Cells, Fibrosis, Vascular Endothelial Growth Factor Receptor-2, Mice, Inbred C57BL, Disease Models, Animal, Endothelium metabolism, Microvessels, Myocardium / cytology, Transcriptome
Description: Vascular complications contribute significantly to the extensive morbidity and mortality rates observed in people with diabetes. Despite well known that the diabetic kidney and heart exhibit imbalanced angiogenesis, the mechanisms implicated in this angiogenic paradox remain unknown. In this study, we examined the angiogenic and metabolic gene expression profile (GEP) of endothelial cells (ECs) isolated from a mouse model with type1 diabetes mellitus (T1DM).ECs were isolated from kidneys and hearts of healthy and streptozocin (STZ)-treated mice. RNA was then extracted for molecular studies. GEP of 84 angiogenic and 84 AMP-activated Protein Kinase (AMPK)-dependent genes were examined by microarrays. Real time PCR confirmed the changes observed in significantly altered genes. Microvessel density (MVD) was analysed by immunohistochemistry, fibrosis was assessed by the Sirius red histological staining and connective tissue growth factor (CTGF) was quantified by ELISA.The relative percentage of ECs and MVD were increased in the kidneys of T1DM animals whereas the opposite trend was observed in the hearts of diabetic mice. Accordingly, the majority of AMPK-associated genes were upregulated in kidneys and downregulated in hearts of these animals. Angiogenic GEP revealed significant differences in Tgfβ, Notch signaling and Timp2 in both diabetic organs. These findings were in agreement with the angiogenesis histological assays. Fibrosis was augmented in both organs in diabetic as compared to healthy animals.Altogether, our findings indicate, for the first time, that T1DM heart and kidney ECs present opposite metabolic cues, which are accompanied by distinct angiogenic patterns. These findings enable the development of innovative organ-specific therapeutic strategies targeting diabetic-associated vascular disorders.
Document Type: Article
Other literature type
File Description: application/pdf
ISSN: 1421-9778
1015-8987
DOI: 10.33594/000000036
Access URL: https://pubmed.ncbi.nlm.nih.gov/30897318
https://doaj.org/article/2c0377b02adf40b4805d0711d63b6be8
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453785
https://pubmed.ncbi.nlm.nih.gov/30897318/
https://europepmc.org/article/MED/30897318
https://hdl.handle.net/10316/106854
https://hdl.handle.net/10216/136304
Rights: CC BY NC ND
Accession Number: edsair.doi.dedup.....c9d1364b9d3fc8758322a6e32b5be277
Database: OpenAIRE
Description
Abstract:Vascular complications contribute significantly to the extensive morbidity and mortality rates observed in people with diabetes. Despite well known that the diabetic kidney and heart exhibit imbalanced angiogenesis, the mechanisms implicated in this angiogenic paradox remain unknown. In this study, we examined the angiogenic and metabolic gene expression profile (GEP) of endothelial cells (ECs) isolated from a mouse model with type1 diabetes mellitus (T1DM).ECs were isolated from kidneys and hearts of healthy and streptozocin (STZ)-treated mice. RNA was then extracted for molecular studies. GEP of 84 angiogenic and 84 AMP-activated Protein Kinase (AMPK)-dependent genes were examined by microarrays. Real time PCR confirmed the changes observed in significantly altered genes. Microvessel density (MVD) was analysed by immunohistochemistry, fibrosis was assessed by the Sirius red histological staining and connective tissue growth factor (CTGF) was quantified by ELISA.The relative percentage of ECs and MVD were increased in the kidneys of T1DM animals whereas the opposite trend was observed in the hearts of diabetic mice. Accordingly, the majority of AMPK-associated genes were upregulated in kidneys and downregulated in hearts of these animals. Angiogenic GEP revealed significant differences in Tgfβ, Notch signaling and Timp2 in both diabetic organs. These findings were in agreement with the angiogenesis histological assays. Fibrosis was augmented in both organs in diabetic as compared to healthy animals.Altogether, our findings indicate, for the first time, that T1DM heart and kidney ECs present opposite metabolic cues, which are accompanied by distinct angiogenic patterns. These findings enable the development of innovative organ-specific therapeutic strategies targeting diabetic-associated vascular disorders.
ISSN:14219778
10158987
DOI:10.33594/000000036