It was originally described to be translocated in a subset of renal carcinomas ( Argani et al., 2005) and deregulated in melanomas and several carcinomas ( Astanina et al., 2020). Transcription factor EB (TFEB) belongs to the microphthalmia (MiT) gene family of bHLH-leucine zipper transcription factors, which includes microphthalmia-associated transcription factor (MITF), TFE3 and TFEC.

Activation of endothelial autophagy, as in other cell types, is mediated by different signaling pathways that are capable of regulating the autophagy-related gene complex, which controls various stages of the process as well as autophagosome formation and elongation, vesicle trafficking, and autophagosome lysosome fusion ( Choi et al., 2013). Moreover, autophagy occurs on the basis of dynamic EC responses to changing environments, angiogenic cues, or intrinsic and extrinsic insults or injuries (such as metabolic stress, redox homeostasis and hypoxia). Consequently, the vascular unit and, in particular, ECs undergo different genetic programs ( Mantovani et al., 1997) regulated by specific transcription factors that adjust the transcriptional landscape to properly respond to different pathophysiological stimuli ( De Val and Black, 2009 Park et al., 2013 Vanlandewijck et al., 2018).Д®merging evidence underlines autophagy as a key cellular mechanism involved in vessel development and physiological and pathological angiogenesis ( Schaaf et al., 2019). Located at the interface between the bloodstream and tissues, the vascular unit orchestrates bidirectional information by integrating humoral, mechanical and cellular cues during the embryonic organogenesis process and in adults this unit also plays a role in communicable and non-communicable diseases ( Peng et al., 2019).

The vascular unit is characterized by endothelial cells (ECs) lying on a basal membrane, where pericytes are embedded. Then, we analyze the current knowledge of TFEB in the vascular system, placing particular emphasis on its regulatory role in angiogenesis and on the involvement of the vascular unit in inflammation and atherosclerosis. Here, we first summarize the general principles and mechanisms by which TFEB activates its transcriptional program. However, emerging findings highlight that TFEB activates other genetic programs involved in cell proliferation, metabolism, inflammation and immunity.

The canonical transcriptional pathway orchestrated by TFEB adapts cells to stress in all kinds of tissues by supporting lysosomal and autophagosome biogenesis. It belongs to the bHLH-leucine zipper transcription factor microphthalmia family, which includes microphthalmia-associated transcription factor, transcription factor E3 and transcription factor EC, and is known to be deregulated in cancer. Transcription factor EB (TFEB) represents an emerging player in vascular biology.

2Laboratory of Vascular Oncology, Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Italy.

1Department of Oncology, University of Torino, Candiolo, Italy.

Gabriella Doronzo 1,2, Elena Astanina 1,2 and Federico Bussolino 1,2*

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