Review Article | Published:

Vascular heterogeneity and specialization in development and disease

Nature Reviews Molecular Cell Biology volume 18, pages 477494 (2017) | Download Citation

Abstract

Blood and lymphatic vessels pervade almost all body tissues and have numerous essential roles in physiology and disease. The inner lining of these networks is formed by a single layer of endothelial cells, which is specialized according to the needs of the tissue that it supplies. Whereas the general mechanisms of blood and lymphatic vessel development are being defined with increasing molecular precision, studies of the processes of endothelial specialization remain mostly descriptive. Recent insights from genetic animal models illuminate how endothelial cells interact with each other and with their tissue environment, providing paradigms for vessel type- and organ-specific endothelial differentiation. Delineating these governing principles will be crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.

Key points

  • Blood and lymphatic vessels are lined by a single layer of endothelial cells (ECs), the molecular signatures and functional properties of which are dependent on the type of vessel and the tissue in which they reside.

  • Depending on the developmental state, vascular bed or (patho)physiological context, blood and lymphatic vessels can form through different mechanisms and can arise from various cellular origins. Heterogeneity in endothelial origin may contribute to the tissue-specific formation and specialization of vessels.

  • Vessel- and organ-specific specialization is governed partly by cell-intrinsic developmental pathways and transcriptional programmes, which control processes such as EC differentiation, proliferation and growth.

  • Tissue microenvironment has an important role in co-determining blood and lymph vessel heterogeneity. Key elements of these environmental signals are mechanical forces, metabolism, cell–matrix and cell–cell interactions, as well as organotypic growth factors that adapt vessel size, shape and function to the needs of the underlying tissue.

  • Vessels reciprocally instruct tissue differentiation and function by producing 'angiocrine' factors that act on cells in their vicinity.

  • Diseases arising from primary abnormalities in ECs, including vascular malformations, often affect a specific vessel type or vascular bed. It remains unclear what determines such organ- and vessel-type specific disease manifestations.

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Acknowledgements

There is much outstanding work in the field that could not be cited in this Review owing to space constraints and so the authors ask the forbearance of their colleagues. The authors thank M. Fiedler for assistance with the artwork. M.P. is supported by the Max Planck Society, the European Research Council (ERC) Starting Grant ANGIOMET (311546), the Deutsche Forschungsgemeinschaft (SFB 834), the Excellence Cluster Cardiopulmonary System (EXC 147/1), the LOEWE grant Ub-Net, the DZHK (German Center for Cardiovascular Research), the Stiftung Charité and the European Molecular Biology Organization Young Investigator Programme. The work of T.M. is funded by the Swedish Research Council, the Swedish Cancer Foundation, the European Research Council (ERC-2014-CoG-646849) and Knut and Alice Wallenberg Foundation.

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Affiliations

  1. Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Ludwigstr. 43, D-61231 Bad Nauheim, Germany.

    • Michael Potente
  2. International Institute of Molecular and Cell Biology, 02–109 Warsaw, Poland.

    • Michael Potente
  3. DZHK (German Center for Cardiovascular Research), partner site Frankfurt Rhine-Main, D-13347 Berlin, Germany.

    • Michael Potente
  4. Department of Immunology, Genetics, and Pathology, Uppsala University, Dag Hammarskjölds väg 20, 75185 Uppsala, Sweden.

    • Taija Mäkinen

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael Potente or Taija Mäkinen.

Glossary

Fenestrated endothelium

Endothelium that is permeated with pores (fenestrae).

Basement membrane

(BM). Sheet-like extracellular matrix structure that separates endothelium from the underlying tissue.

Blood–brain barrier

(BBB). A selective permeability barrier that restricts the passage of solutes from the circulating blood to the brain.

Tight junctions

Intercellular junctional complexes that are composed of claudins, occludin and junctional adhesion molecules, and that function as diffusion barriers.

Adherens junctions

Adhesive structures that are formed through the association of cadherins, which link actin filaments between cells.

Transcytosis

Transport of macromolecules across the cell.

Stem cell niche

A microenvironment that supports the undifferentiated and self-renewable state of stem cells.

Angioblasts

Endothelial cell precursor cells that differentiate from the mesoderm and form the first embryonic blood vessels.

Mesoderm

The middle layer of the three germ layers in the early embryo, which forms connective tissues (including endothelium) and muscle.

Lumen formation

The formation of the interior space of a vessel through which blood or lymph flows.

Membrane blebbing

Bulge or protrusion of the plasma membrane, which is characterized by a spherical morphology.

Progenitor cells

Early descendants of stem cells that can divide a limited number of times and can differentiate into a few cell types.

Haemogenic endothelium

Specialized endothelial cells present in certain embryonic blood vessels, which can give rise to haematopoietic cells during a restricted window of development.

Transmural flow

Fluid flow through the endothelial layer.

Glycolysis

An oxygen-independent metabolic pathway that converts glucose into pyruvate to generate energy and biomass precursors.

Fatty acid β-oxidation

(FAO). A catabolic process in mitochondria during which fatty acids are broken down to generate substrates for the tricarboxylic acid (TCA) cycle and the electron transport chain.

Notochord

A transient midline structure that forms in chordate embryos, and which provides signals for the patterning of the surrounding tissues.

Haemangiomas

Benign vascular tumours that are composed of an increased number of endothelial cells.

Endothelial glycocalyx

Coating of the apical surface of endothelial cells, which is composed of proteoglycans and glycoproteins and which has a role in mechanotransduction, signalling, haemostasis and blood cell interactions.

Primary cilia

A non-motile microtubule-based antenna-like sensory and signalling organelle.

Glaucoma

A group of eye diseases that is caused by damage to the optic nerve and that results in loss of vision.

Lymphoedema

Fluid accumulation and tissue swelling due to dysfunction of the lymphatic vessels.

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DOI

https://doi.org/10.1038/nrm.2017.36

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