Endothelial Cell-Pericyte Crosstalk: Novel Interactions for Generating Stable and Functional Blood Vessels in Ischaemia

Abstract

Peripheral artery disease (PAD) affects over 230 million people globally. This atherosclerotic disease reduces blood perfusion to the lower extremities causing ischaemia and in severe cases lead to gangrene and limb amputation. One way to increase blood perfusion is by angiogenesis which is the generation of new blood vessels from pre-existing vessels. In this process endothelial cells (ECs) form a tubular structure and pericytes wrap around to stabilise newly formed microvessels.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pleiotropic cytokine that binds to 2 signalling receptors, DR4 and DR5. TRAIL has non-apoptotic functions in the vasculature that promotes cell survival. We previously showed that Trail-/- mice had impaired angiogenesis in a preclinical model of PAD. How TRAIL regulates angiogenesis to form stable blood vessels is still unclear, and whether TRAIL derived from ECs and TRAIL receptors contribute to this process is unknown.

This thesis discovered: (i) TRAIL and DR5 expression and interaction is augmented in human ECs exposed to hypoxia. (ii) DR5 activation on human ECs is required to stimulate angiogenic processes. (iii) The endothelium is a major source of TRAIL in healthy circulation that is compromised in PAD. (iv) EC-derived TRAIL stimulates angiogenesis, pericyte recruitment and wrapping around tubules necessary for vessel stabilisation. (v) Agonistic anti-mouse and anti-human DR5 mAb stimulates sprouting in blood vessels harvested from mice and from PAD patient’s ex vivo.

This thesis identified novel EC-specific and TRAIL-dependent effects in angiogenesis and vessel stabilisation. Proof-of-concept study showed that agonistic DR5 mAb could be used to limit ischaemia reduction in PAD by stimulating angiogenesis and vessel stabilisation. These substantial findings not only provide new knowledge to TRAIL’s non cytotoxic functions in the vasculature but highlight a new and more timely treatment of PAD.