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Extracellular control of TGFβ signalling in vascular development and disease

Key Points

  • Transforming growth factor-β (TGFβ) isoforms are synthesized as precursor proteins that are proteolytically processed and secreted by cells in an inactive form. Latent TGFβ complexes, which are bound via large latent TGFβ-binding proteins (LTBPs) to fibrillin-1, are sequestered and can be rapidly released by proteases in response to tissue perturbations.

  • TGFβs initiate diverse cellular responses by binding to and activating specific type I and type II Ser/Thr kinase receptors and intracellular SMAD effectors. TGFβs regulate the function of endothelial and vascular smooth muscle cells (and many other cell types) in a highly context-dependent manner.

  • The vital importance of TGFβ signalling in vascular development was recognized when several human vascular pathologies were associated with mutations in TGFβ receptor genes, and mouse models that were deficient in Tgfbr1 or TGFβ receptors were found to have severe angiogenesis defects that caused embryonic lethality.

  • Transgenic mouse models of Marfan syndrome exposed a surprising and crucial function of elastic extracellular matrix components in regulating TGFβ signalling.

  • By interacting with unprocessed TGFβ, emilin-1 protects TGFβ from proteolytic processing by furin endoprotease and inhibits TGFβ signalling. Loss of emilin-1 leads to a reduction in the arterial lumen diameter with a resultant increase in vascular resistance and hypertension due to excessive TGFβ signalling.

  • Elevated levels of the soluble TGFβ co-receptor endoglin cause endothelial dysfunction and have been coupled to pre-eclampsia.

  • In summary, a growing number of studies show that extracellular control of TGFβ signalling is vital for both development and maintenance of the vasculature.

Abstract

The intracellular mechanism of transforming growth factor-β (TGFβ) signalling via kinase receptors and SMAD effectors is firmly established, but recent studies of human cardiovascular syndromes such as Marfan syndrome and pre-eclampsia have refocused attention on the importance of regulating the availability of active extracellular TGFβ. It seems that elastic extracellular matrix (ECM) components have a crucial role in controlling TGFβ signalling, while soluble and membrane bound forms of TGFβ co-receptors add further layers of regulation. Together, these extracellular interactions determine the final bioavailability of TGFβ to vascular cells, and dysregulation is associated with an increasing number of vascular pathologies.

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Figure 1: Signal transduction by TGFβ family members.
Figure 2: Regulation of TGFβ bioavailability.
Figure 3: TGFβ signalling in vasculogenesis and angiogenesis.
Figure 4: Vascular remodelling in PAH and HHT.
Figure 5: TGFβ-associated defects in Marfan and Loeys–Dietz syndromes.

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Acknowledgements

Research in our laboratories is supported by grants from the Dutch Cancer Society, the EC (Angiotargeting and Tumour Host Genomics), the Ludwig Institute for Cancer Research, the Netherlands Organization for Scientific Research, the British Heart Foundation, Newcastle Hospital Trustees, the Cookson Foundation and the Wellcome Trust. We are grateful to our colleagues for valuable discussion, and apologize to those whose contributions have not been cited because of space constraints.

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DATABASES

OMIM

arterial tortuosity syndrome

Duchenne's muscular dystrophy

familial thoracic aneurysm disorder

hereditary haemorrhagic telangiectasia type 1

HHT type 2

Loeys-Dietz syndrome

Marfan syndrome

MFS type 2

pulmonary arterial hypertension

FURTHER INFORMATION

Peter ten Dijke's homepage

Helen Arthur's homepage

HHT Foundation International web site

The US National Marfan Foundation web site

Glossary

Pleiotropic

Influencing multiple different traits.

Convertase family of endoproteases

A group of enzymes that make an internal cut in a polypeptide chain to convert it from an inactive to an active form.

Fibrillin

An extracellular matrix glycoprotein that is a structural component of microfibrils.

Microfibril

A fibre component (10 nm in diameter) of the extracellular matrix that is essential for the integrity of elastic fibres, which are particularly abundant in the aorta.

Matrix metalloprotease

One of a family of structurally related extracellular Ca2+-dependent zinc-containing proteases involved in tissue remodelling and ECM degradation.

RGD sequence

An amino acid sequence (Arg-Gly-Asp) found in extracellular matrix proteins that directly binds to integrins.

Morpholino

Chemically synthesized oligonucleotide analogues used to knock down gene expression by specifically binding to target transcripts to inhibit RNA splicing or translation.

Vessel muscularization

The development of smooth muscle cells around a vessel to support and stabilize it.

Pericyte

A smooth muscle-like cell that is intimately associated with endothelial cells of small blood vessels.

Mesenchymal cell

A member of a heterogeneous multipotent cell population that arises mainly from embryonic mesoderm.

Hypertension

Elevated blood pressure.

Arteriovenous malformation

(AVM). Abnormal communication between an artery and a vein producing dilated vessels.

Intussusceptive angiogenesis

The process of blood vessel growth by 'splitting' — the wall of an existing blood vessel extends into the lumen to split a single vessel in two.

Sprouting angiogenesis

The process by which endothelial cells migrate and proliferate into the surrounding matrix to form new vessel branches in response to an angiogenic stimulus.

Anastomosis

A naturally occurring arteriovenous connection that may be dynamically regulated and is particularly frequent in thermoregulatory vascular beds.

Placental syncytiotrophoblast cell

A multinucleated cell found at the boundary of the fetal and maternal layers of the placenta.

Truncus arteriosus

A single vessel that forms early in development and then septates to form the aorta and pulmonary trunk. A persistent truncus arteriosus is one that has failed to septate, compromising the separation of pulmonary and systemic circulations.

Aortopulmonary septation

The process whereby the pulmonary trunk and aorta separate during development.

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ten Dijke, P., Arthur, H. Extracellular control of TGFβ signalling in vascular development and disease. Nat Rev Mol Cell Biol 8, 857–869 (2007). https://doi.org/10.1038/nrm2262

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