SurveyEmerging role of bone morphogenetic proteins in angiogenesis
Introduction
Angiogenesis is the formation of new blood capillaries from a pre-existing capillary network. It is active during embryonic development and is normally quiescent at the adult stage except for oestrous cycle-dependent vascularization of the ovaries and uterus and placental development during pregnancy. However, angiogenesis is re-activated during wound repair and under several pathological conditions, such as tumour growth and metastasis and cardiovascular disorders [1]. Angiogenesis is a multistep process that can be roughly divided into two phases (Fig. 1). During the initial activation phase, the perivascular basement membrane is degraded, endothelial cells migrate into the extracellular space, proliferate, form capillary sprouts and self-organize into tubular structures. This is followed by a maturation/stabilization phase, when endothelial cells cease migration and proliferation, the basement membrane is reconstituted and smooth muscle cells/pericytes are recruited and apposed to the neo-vessels, thereby reconstituting vessel wall integrity. A balance of pro- and anti-angiogenic factors very tightly regulates angiogenesis. Important pro-angiogenic factors include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), which stimulate proliferation and migration of endothelial cells. The angiopoietins (Ang) also play an important role but their effects are more complex and they are involved in the two phases: Ang1, through its receptor Tie2, is involved in vascular quiescence while Ang2, by antagonizing Ang1 binding to Tie2, is involved in the activation phase of angiogenesis. Platelet-derived growth factor (PDGF) is a stabilizing factor that mediates the vascular recruitment of pericytes and smooth muscle cells. Transforming growth factor beta (TGFβ) has also been shown to be involved in extracellular matrix accumulation as well as in the regulation of endothelial cell functions and smooth muscle differentiation. Several recent reviews have discussed the role of TGFβ and TGFβ family members in angiogenesis [2], [3]. In the present review, we will focus our interest on the subgroup of the TGFβ family constituted by the bone morphogenetic proteins (BMPs), as recent data clearly demonstrate their direct roles in angiogenesis.
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BMPs and BMP receptors: structural features and sites of expression
Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which includes TGFβs, activins/inhibins, nodal, myostatin, anti-Müllerian hormone (AMH) and growth and differentiation factors (GDFs). More than 15 BMP-related proteins have been identified and subdivided into several groups based on their amino acid sequence similarity and their functions [4]. BMP2, BMP4, and the Drosophila dpp form one subgroup (BMP2/4 subgroup). Members of this subgroup have a wide range of biological
Knowledge from human vascular diseases
A clear demonstration of the implication of BMPs in angiogenesis comes from the causal implication of mutations of BMP receptors in several human vascular genetic diseases.
The first vascular disease related to BMPs is the Rendu–Osler–Weber syndrome also known as hemorrhagic hereditary telangiectasia (HHT). HHT is an autosomal dominant vascular disorder, in which the patients develop mucosal and skin telangiectasia, pulmonary, cerebral and hepatic malformations, and hemorrhages associated with
Effects of BMPs signalling through ALK2, ALK3 and ALK6: implication in the activation phase of angiogenesis
GDF5 was the first BMP reported to have a role in angiogenesis. GDF5 enhances angiogenesis in the chorio-allantoic membrane (CAM) assay and in the rabbit cornea assay [57]. In the same study, it was found that the addition of GDF5 accelerated the migration of bovine aortic endothelial cells (BAEC) while it did not affect their proliferation.
In contrast, BMP2 was initially described to have no effect in the CAM and in the rabbit cornea assays [57]. Later on, another group found that BMP2
Effects of BMPs signalling through ALK1 (BMP9 and 10): implication in the maturation phase of angiogenesis
For a number of years, in the absence of a specific ligand for ALK1, several groups have bypassed this problem by expressing a constitutively active form of ALK1 (ALK1ca) in primary endothelial cells and have reached different conclusions. Using HUVECs, Ota et al. found that ALK1ca expression inhibited endothelial cell proliferation while it had no effect on tube formation in collagen gels [79]. Goumans et al., using MECs, showed that ALK1ca expression increased migration [80]. In contrast, we
Smad-dependent and Smad-independent BMP signalling
Taken together these data demonstrate that BMPs, signalling through ALK3 and ALK6, inhibit VSMC proliferation and increase VSMC migration while they inhibit endothelial cell proliferation and migration. In contrast, BMP9/10, signalling more specifically through ALK1, inhibit endothelial cell proliferation and migration. As these receptors all induce the Smad1/5/8 pathway, it would suggest that Smad-independent signalling pathways are also involved. BMPs have been found to regulate a variety of
BMP antagonists and co-receptors
Ligand-receptor interaction can be inhibited by secreted antagonists including noggin, chordin, follistatin and the DAN/Cerberus family of proteins or can be activated through co-receptors. Some of these extracellular regulators appear to have dual functions and are therefore difficult to classify into one specific group. Some extracellular regulators have been recently described to play a role in angiogenesis [93].
Conclusion and possible therapeutic applications of BMPs in pathological angiogenesis
The data that we have discussed in this review clearly place BMPs as important players in angiogenesis. Overall, BMPs from the GDF5, BMP2 and BMP7 subgroups, signalling through ALK2, ALK3 or ALK6, increase endothelial cell proliferation and migration while they inhibit VSMC proliferation, induce VSMC migration and maintain VSMC differentiation. These data suggest that these BMPs, through their actions on endothelial cells, are important actors of the activation phase of angiogenesis and,
Acknowledgments
We apologize to those whose work was not cited due to space limitation. Our studies are supported by INSERM, CEA and by ARC (Association pour la Recherche sur le Cancer).
Laurent David obtained his MSc and PhD degrees in Cellular and Molecular Biology at Université Joseph Fourier (Grenoble, France), respectively in 2003 and 2007. During his PhD, he characterized the specific ligands of the orphan receptor ALK1: BMP9 and BMP10. After that, he demonstrated that BMP9 was a circulating factor and a negative regulator of angiogenesis. Those results lead to the conclusion that BMP9 might be a regulator of endothelium quiescence. He is now a post-doctoral fellow in
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Laurent David obtained his MSc and PhD degrees in Cellular and Molecular Biology at Université Joseph Fourier (Grenoble, France), respectively in 2003 and 2007. During his PhD, he characterized the specific ligands of the orphan receptor ALK1: BMP9 and BMP10. After that, he demonstrated that BMP9 was a circulating factor and a negative regulator of angiogenesis. Those results lead to the conclusion that BMP9 might be a regulator of endothelium quiescence. He is now a post-doctoral fellow in Jeff Wrana's Lab (Toronto, Canada), where he is working on TGFβ signalling in cancer and embryonic stem cells.
Jean-Jacques Feige is a senior researcher in angiogenesis and growth factor research at the Institut National de la Santé et de la Recherche Médicale (INSERM) in Grenoble, France and Head of the INSERM Unit 878. He graduated from the Institut National des Sciences Appliquées in Lyon in 1977 and obtained his PhD at the University of Grenoble-1 in 1981. He was appointed by INSERM in 1984. Between 1986 and 1988, Dr Feige visited the Department of Cell Biology at the University of California San Diego (USA) and the Salk Institute for Biological Studies (La Jolla, CA, USA, Laboratory of Pr R. Guillemin). In 2001, he established his own lab in Grenoble. He has a long-standing scientific experience in the field of growth factor research and, for many years, he has been working on the role of growth factors (FGF-2, TGFβ, VEGF, EG-VEGF and BMPs) in the control of endocrine functions, fibrosis and essentially angiogenesis. He has published more than 120 scientific publications and reviews in peer-reviewed journals.
Sabine Bailly is a senior researcher in growth factor research and angiogenesis at the Institut National de la Santé et de la Recherche Médicale (INSERM U878) in Grenoble, France. She graduated from the University of Sciences of Paris-Sud and obtained her PhD in 1991 in X. Bichat Hospital in Paris on inflammatory cytokines. She performed a post-doctoral training in the Department of Molecular Biology at the Royal Hallamshire Hospital in Sheffield (England) between 1992 and 1993. She was appointed by INSERM in 1994. In 1995, she joined the laboratory of Dr Jean-Jacques Feige in Grenoble and has worked since on the function and signal transduction pathways of growth factors of the TGFβ family, first in endocrinology and more recently in angiogenesis. She has published 38 scientific publications and reviews on peer-reviewed journals.
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