MEOX2/TCF15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake
MEOX2/TCF15 heterodimeren programmeren het capillaire endotheel van het hart voor vetzuuropname
Coppiello, Giulia; S0197747
Capillary endothelial cells (ECs) in different organs are specialized to fulfill the particular needs of parenchymal cells with which are in direct contact. Specific information about the molecular and functional specialization of heart capillary ECs is currently limited to their documented role in the control of cardiac contractility through secretion of inotropic molecules and control of ion fluxes. Growing evidence however suggests that heart ECs play an active role in transport of fatty acids (FAs) a principal energy source for the heart to cardiomyocytes and that extrinsic and intrinsic cues regulate the expression of transporter molecules to support this role. Nevertheless, this is still a new concept rather than an accepted paradigm, and the molecular players involved are not completely understood.Using microarray profiling on freshly isolated ECs from heart, brain and liver, we revealed a genetic signaturefor microvascular heart ECs and identified MEOX2/TCF15 heterodimers as novel transcriptional determinants. This signature was largely shared with ECs from skeletal muscle and adipose tissue, two organs that are justlike the heart involved in FA handling and was enriched in genes encoding FA transport-related proteins. Using gain- and loss-of- function approaches in cultured cells and transgenic mice, 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 heartECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs, resulting in reduced FA transfer to cardiomyocytes. In the long term this combined haplodeficiency resulted in impaired cardiac contractility.Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil two 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.