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  • Review Article
  • Published:

Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis

Nature Reviews Drug Discovery volume 15, pages 125–142 (2016)Cite this article

Subjects

Key Points

  • Modalities of cell–cell communication of relevance to angiogenesis, inflammation and fibrosis include paracrine signalling, mechanosignalling, direct signal transduction via gap junctions and tunnelling nanotubes, and communication via the release and uptake of exosomes. Intercellular communication might be targeted by altering gap junctions and nanotubes, and exosomes are potential drug delivery vehicles as well as diagnostic markers.

  • Leukocytes interact with microvascular cells to affect angiogenesis. These interactions are potentially druggable processes for the regulation of angiogenesis.

  • Angiogenesis can occur through three different mechanisms — sprouting, intussusception and looping — which should be taken into account when designing new pharmacological treatments to reduce or increase angiongesis.

  • Different classes of leukocytes are potential targets to reduce uncontrolled fibrosis. Inhibited recruitment of inflammatory leukocytes together with on-site reprogramming of macrophages could promote fibrosis resolution.

  • In response to different signals from the environment, such as interferons, Toll-like receptor ligands or interleukins, macrophages undergo classical (M1) or alternative activation, which results in a continuum of diverse phenotypes depending on activation states. The identification of the underlying regulation of macrophage plasticity and polarized activation provides targets for macrophage-centred therapies.

  • Delineation of the endothelial heterogeneity is important to the development of strategies for the targeted delivery of drugs to organ-specific vascular beds to limit adverse effects.

Abstract

Regulation of vascular permeability, recruitment of leukocytes from blood to tissue and angiogenesis are all processes that occur at the level of the microvasculature during both physiological and pathological conditions. The interplay between microvascular cells and leukocytes during inflammation, together with the emerging roles of leukocytes in the modulation of the angiogenic process, make leukocyte–vascular interactions prime targets for therapeutics to potentially treat a wide range of diseases, including pathological and dysfunctional vessel growth, chronic inflammation and fibrosis. In this Review, we discuss how the different cell types that are present in and around microvessels interact, cooperate and instruct each other, and in this context we highlight drug targets as well as emerging druggable processes that can be exploited to restore tissue homeostasis.

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Figure 1: Cells that affect angiogenesis at the level of the microvasculature.
Figure 2: The different mechanisms of angiogenesis — sprouting, splitting and looping.
Figure 3: The different stages of the leukocyte recruitment cascade and the potential drug targets central to leukocyte recruitment.
Figure 4: Processes related to vascular and leukocyte communication that can be targeted to combat inflammation and fibrosis.

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Acknowledgements

The authors would like to thank the members of their laboratories and many of their colleagues, especially L. Claesson-Welsh, A. Moustakas and M. Welsh for sharing their insights and for stimulating discussions. The authors apologize to all colleagues whose relevant work has not been cited owing to space limitations. The authors are supported by the Swedish Medical Research Council, the Swedish Cancer Society, the Royal Swedish Academy of Sciences, the Swedish Diabetes Foundation, the Swedish Foundation for Strategic Research, the Novo Nordisk Foundation, the Ragnar Söderberg foundation, the Knut and Alice Wallenberg Foundation, the Ruth and Nils-Erik Stenbäcks Foundation, the Foundations for Proteoglycan Research, the Marie Sklodowska-Curie Innovative Training Network InCeM (Integrated Component Cycling in Epithelial Cell Motility) and Uppsala University.

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  1. Department of Medical Cell Biology, Uppsala University, Husargatan 3, Uppsala, 75123, Sweden

    Johan Kreuger & Mia Phillipson

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  1. Johan Kreuger
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Correspondence to Mia Phillipson.

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Glossary

Leukocytes

White blood cells of the immune system. Different classes of leukocytes may fight infections or modulate processes such as angiogenesis, inflammation and fibrosis.

Mural cells

The vascular smooth muscle cells and pericytes that surround and support endothelial cells.

Tunnelling nanotubes

Very thin cytoplasmic extensions containing actin that connect various cell types to allow direct exchange of intracellular components.

Intravital microscopy

A microscopy technique that enables direct observations of biological processes in vivo.

Extravasation

Emigration of immune cells from the vasculature into the surrounding tissue.

Immunoliposomes

Antibody-conjugated spheres of phospholipids that can be used to deliver drugs to tissues.

Alternatively activated macrophages

These macrophages are less efficient at killing bacteria and are activated by different cytokines than are the classic M1 inflammatory macrophages. Alternatively activated macrophages are involved in tissue remodelling, wound healing, angiogenesis and tumour progression.

Inside-out signalling

Leukocyte integrin inside-out signalling occurs following chemokine receptor ligation and activates the ligand-binding function of the integrins.

Outside-in signalling

Integrin outside-in signalling occurs following the binding of leukocyte integrins to their counter-receptors on the endothelium and results in cytoskeletal rearrangements, strengthening of adhesion, cell spreading and migration.

Epithelial–mesenchymal transition

A process in which normally stationary epithelial cells lose cell–cell adhesions and cell polarity, thus becoming migratory.

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Kreuger, J., Phillipson, M. Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis. Nat Rev Drug Discov 15, 125–142 (2016). https://doi.org/10.1038/nrd.2015.2

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