Meox2/Tcf15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake.
BACKGROUND
Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking.


METHODS AND RESULTS
Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport-related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility.


CONCLUSIONS
Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.
['Coppiello|Giulia|G|', 'Collantes|Maria|M|', 'Sirerol-Piquer|María Salomé|MS|', 'Vandenwijngaert|Sara|S|', 'Schoors|Sandra|S|', 'Swinnen|Melissa|M|', 'Vandersmissen|Ine|I|', 'Herijgers|Paul|P|', 'Topal|Baki|B|', 'van Loon|Johannes|J|', 'Goffin|Jan|J|', 'Prósper|Felipe|F|', 'Carmeliet|Peter|P|', 'García-Verdugo|Jose Manuel|JM|', 'Janssens|Stefan|S|', 'Peñuelas|Iván|I|', 'Aranguren|Xabier L|XL|', 'Luttun|Aernout|A|']
D000273:Adipose Tissue D000818:Animals D051792:Basic Helix-Loop-Helix Transcription Factors D018955:CD36 Antigens D002303:Cardiac Output, Low D002478:Cells, Cultured D003331:Coronary Vessels D042783:Endothelial Cells D050556:Fatty Acid-Binding Proteins D005227:Fatty Acids D005947:Glucose D006579:Heterozygote D018398:Homeodomain Proteins D006801:Humans D008071:Lipoprotein Lipase D008079:Lipoproteins, VLDL D051379:Mice D008810:Mice, Inbred C57BL D009206:Myocardium D025941:Protein Interaction Mapping D034741:RNA, Small Interfering D046888:Tissue Array Analysis D059467:Transcriptome
heart endothelium fatty acids metabolism transcription factors