Abstract

Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. Autophagy is essential for recycling nutrients, generating energy to maintain cell viability in most tissues and during adverse conditions such as hypoxia/ischaemia. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. Preserved autophagic flux within the ECs has an essential role in maintaining their physiological characteristics, whereas defective autophagy can promote endothelial pro-inflammatory and atherogenic phenotype. However, we still lack a good knowledge of the complete molecular repertoire controlling various aspects of endothelial autophagy and how this is associated with vascular diseases. Here, we provide an overview of the current state of the art of autophagy in ECs. We review the discoveries that have so far defined autophagy as an essential mechanism in vascular biology and analyse how autophagy influences ECs behaviour in vascular disease. Finally, we emphasise opportunities for compounds to regulate autophagy in ECs and discuss the challenges of exploiting them to resolve vascular disease.

Highlights

  • Autophagy is the primary intracellular degradation system of cytoplasmic materials through the lysosomes

  • Macroautophagy consists of multiple steps, including initiation, elongation and maturation of autophagosomes, which are controlled by autophagy-related genes (ATG) [6] and regulated by one of the major anabolic pathway, the multimeric protein mammalian target of rapamycin complex 1 [7]. mTORC1 complex includes the serine/threonine (Ser/ Thr) kinase mTOR, the regulatory protein RAPTOR, the assembly factor mLST8 and two inhibitory subunits: PRAS40 and DEPTOR

  • Recent research demonstrated that vascular endothelial growth factor (VEGF) activates autophagic flux by an AMP-activated protein kinase (AMPK)-dependent mechanism [33]

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Summary

Edinburgh Research Explorer

Autophagy at the interface of endothelial cell homeostasis and vascular disease Citation for published version: Mameli, E, Martello, A & Caporali, A 2021, 'Autophagy at the interface of endothelial cell homeostasis and vascular disease', Febs Journal. Autophagy at the interface of endothelial cell homeostasis and vascular disease Eleonora Mameli, Andrea Martello and Andrea Caporali. Keywords autophagy; endothelial cells; inflammation; senescence; therapeutic modulation; vascular disease. Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. We emphasise opportunities for compounds to regulate autophagy in ECs and discuss the challenges of exploiting them to resolve vascular disease

Introduction
Molecular mechanisms of the autophagic process
Autophagy controls endothelial cells homeostasis and functions
Autophagy as a regulator of endothelial cell senescence and inflammation
Dysregulation of autophagy in endothelial cells in vascular disease
Oxygen glucose deprivation
Vascular ischaemic disease
Epigenetic regulation of autophagy in vascular disease
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