Understanding the poor angiogenic capacity of the mammalian heart

Objective: The reason why a hypoxic tumor forms its own vasculature, mainly through the secretion of the Vascular Endothelial Growth Factor (VEGF), whereas an ischemic heart cannot, remains obscure. In this work, we investigated whether cardiac endothelial cells (ECs) lose their capacity to prolifer...

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Bibliographic Details
Published in:Vascular pharmacology 2018-04, Vol.103-105, p.58-59
Main Authors: Kocijan, T., Cappelletto, A., Rehman, M., Tang, Y.Q., Vodret, S., Zentilin, L., Giacca, M., Zacchigna, S.
Format: Article
Language:English
Subjects:
Angiogenesis
Beads
Cancer
Capillaries
Cardiomyocytes
Cardiovascular disease
Cell culture
Coding
Cornea
Embryos
Endothelial cells
Filopodia
Flow cytometry
Fluorescence
Gene expression
Green fluorescent protein
Heart
Hypoxia
Ischemia
Mammals
Muscles
Neonates
Organs
Proteins
Secretion
Skeletal muscle
Tumors
Unmanned aerial vehicles
Vascular endothelial growth factor
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Summary:Objective: The reason why a hypoxic tumor forms its own vasculature, mainly through the secretion of the Vascular Endothelial Growth Factor (VEGF), whereas an ischemic heart cannot, remains obscure. In this work, we investigated whether cardiac endothelial cells (ECs) lose their capacity to proliferate soon after birth, similar to mammalian cardiomyocytes. Methods: The effect of VEGF in embryonic and adult heart and skeletal muscle was analysed by injecting AAV (Adeno-Associated Vector)-encoded VEGF into the three organs. ECs from these organs were isolated using CD31 magnetic beads and analysed by flow cytometry, cell culture assays and RNAseq. Cells isolated from EGFP (Enhanced Green Fluorescent Protein) transgenic pups were injected into skeletal muscle and adult heart. Cancer cells were injected into adult heart and skeletal muscle. Results: VEGF injection in the skeletal muscle and embryonic heart induced significantly more vessel formation compared to the adult heart. Therefore, we wanted to understand whether intrinsic properties of ECs or presence of some inhibitory factors within the adult heart determine the different angiogenic potential of the three organs. Flow cytometry analysis of ECs showed presence of an EC sub-population characterized by high expression levels of tip cell markers, VEGFR2 and CD 105, in the embryonic/neonatal but not in the adult heart ECs. Consistently, formation of filopodia by rip cells and vessel-like tubular structures in response to VEGF was much more evident for embryonic/neonatal then for adult cardiac ECs. RNAseq data from the three EC types reveal a differential expression profile for coding genes, miRNAs and Inc-RNAs. ECs purified from the heart of EGFP transgenic pups formed capillaries and integrated into the vascular network of skeletal muscle but not of adult heart, suggesting the presence of an anti-angiogenic factor in the latter organ. Furthermore, the expression of VEGFR1 and its soluble isoform sFltl was significantly increased in adult compared to embryonic hearts, consistent with the role of sFItt in keeping cornea avascular. Finally, cancer cells injected into the heart of adult mice grew much less compared to the same number of cells injected into the skeletal muscle, possibly indicating that impaired angiogenic potential of the heart inhibited tumor growth. Conclusions: Collectively, these results indicate that both cell-autonomous and non autonomous mechanisms halt the proliferation of ECs in the
ISSN:1537-1891
1879-3649
DOI:10.1016/j.vph.2017.12.032