Brief reviews
Controlling the Angiogenic Switch: A Balance between Two Distinct TGF-b Receptor Signaling Pathways

https://doi.org/10.1016/S1050-1738(03)00142-7Get rights and content

Abstract

Biochemical studies in endothelial cells (ECs) and genetic studies in mice and humans have yielded major insights into the role of transforming growth factor β (TGF-β) and its downstream Smad effectors in embryonic vascular morphogenesis and in the establishment and maintenance of vessel wall integrity. These studies showed that TGF-β signaling is of critical importance for normal vascular development and physiology. They also indicated the involvement of two distinct TGF-β signaling cascades within ECs, namely the activin receptor-like kinase 5 (ALK5)–Smad2/3 pathway and the ALK1–Smad1/5 pathway. Aberrant TGF-β signaling forms the basis for several vascular disorders such as hereditary hemorrhagic telengiectasia and primary pulmonary hypertension as well as neovascularization during tumorigenesis. This review describes the role of TGF-β in angiogenesis and some of the controversial issues concerning TGF-β signaling through ALK1 and ALK5 in ECs.

Section snippets

TGF-b Signaling

Cellular responses to TGF-β are elicited via specific transmembrane type I and type II serine/threonine kinase receptors (Figure 1; Massagué 1998). The signaling pathway is initiated by binding of TGF-β to the constitutively active TGF-β type II receptor (TβRII). Upon ligand binding, TβRII recruits and phosphorylates the TGF-β type I receptor (TβRI) (also known as activin receptor-like kinase 5 [ALK5]). The activated ALK5 transduces the signal to the nucleus by phosphorylating a specific subset

TGF-b and Angiogenesis: Signaling through ALK1 and ALK5

In the vascular system, TGF-β regulates the process of angiogenesis (Figure 2), which involves the activation, remodeling, and expansion of pre-existing networks, such as the primary vascular plexus in the yolk sac and the vasculature in injured tissues during wound healing Carmeliet 2000, Pepper 1997. Vessels are formed by two main cell types—ECs and perimural cells—that enshroud the endothelium. Under normal conditions, the EC forming the capillary wall will become quiescent. It is thought

ALK1 and Id1 in Angiogenesis

Id1 is identified as an ALK1-specific target gene Goumans et al. 2002, Ota et al. 2002. Id1 is a member of a family of helix-loop-helix proteins that do not possess a basic DNA binding domain and inhibit lineage commitment within multiple cell types through sequestration of bHLH transcription factors such as MyoD (Norton 2000). An important role for Id proteins in angiogenesis is demonstrated clearly by loss-of-function studies in mice. Id1/Id3 double knockout mice show abnormal angiogenesis,

Concentration-Dependent Responses to TGF-b; Thresholds versus Use of Different Type I Receptors

Angiogenesis is controlled by multiple growth factors that generate a multitude of signals that need to be coordinated carefully in the cell to guarantee a proper vascular network. Several growth factors have been implicated in the process of angiogenesis, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The effects of TGF-β on angiogenesis are dependent partially on its capacity to modulate the expression levels or activities of these factors. TGF-β

Controversy: Cues from the Environment

The precise role of TGF-β in angiogenesis has proved to be confusing and context dependent. In addition, effects of ALK1 on angiogenesis have not been consistent. Infecting ECs with caALK1 has been shown to either inhibit or stimulate EC proliferation, migration, and cell adhesion Goumans et al. 2002, Lamouille et al. 2002. Differences in the ECs used (arterial versus vein) and the culture conditions may cause these discrepancies. An important determinant is serum. One of the most peculiar

Conclusions

The function of TGF-β in angiogenesis is very context dependent. The spatiotemporal effects mediated by TGF-β on cells are determined by the particular differentiation stage of the cell and the dose of TGF-β present. Research into ALK1 and ALK5 signaling has demonstrated the complexity of the system. Stimulating ECs with TGF-β activates the two type I receptor pathways with different kinetics and threshold levels. ALK1 and ALK5 show clear differences in transcriptional regulation patterns.

Acknowledgements

The authors thank Drs. Peter ten Dijke and Jon Halstead for invaluable discussions and critical reading of the manuscript. They also acknowledge grant support from the Dutch Organization for Scientific Research (MW 902-16-295), the European Union (QLG1-CT-2001-01032), and the Netherlands Heart Foundation (grant 99-046).

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