Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 1053 word(s) 1053 2021-07-16 08:04:58 |
2 Format correct -1 word(s) 1052 2021-07-27 03:32:07 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Ponomarev, L. Bone Morphogenetic Proteins. Encyclopedia. Available online: (accessed on 20 April 2024).
Ponomarev L. Bone Morphogenetic Proteins. Encyclopedia. Available at: Accessed April 20, 2024.
Ponomarev, Ljuba. "Bone Morphogenetic Proteins" Encyclopedia, (accessed April 20, 2024).
Ponomarev, L. (2021, July 26). Bone Morphogenetic Proteins. In Encyclopedia.
Ponomarev, Ljuba. "Bone Morphogenetic Proteins." Encyclopedia. Web. 26 July, 2021.
Bone Morphogenetic Proteins

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix.

BMP BMP pathway fine-tuning lymphatic vessel biology mechano-transduction vascular malformations signaling cross-talk

1. Introduction

Dysfunction of endothelial cells lining the inner wall of the circulatory and lymphatic vasculature is a major cause and amplifier of vascular disease. Mutations in genes encoding different components of the bone morphogenetic protein (BMP) pathway cause rare but severe vascular diseases. Most of these diseases are due to loss of function of BMP signaling [1][2][3], but some vascular anomalies also result (indirectly) from a gain of function of BMP signaling [4]. Together, this underscores that the BMP signaling levels need to be well balanced in vascular development and physiology. Nowadays, the BMP pathway is an important therapeutic target for treatment of vascular diseases [3].

2. Fine-Tuning Mechanisms of BMP Signaling in the Vasculature

The shaping of BMP morphogen gradients or responses depends on the bioavailability of (tissue-specific) BMP ligand–receptor complexes, and intracellular effectors. In addition, the BMP signaling pathway is further fine-tuned by different extracellular and intracellular agonists and antagonists that bind and sequester BMPs or signaling components. In this respect, it is striking how target genes of BMP signaling often function as negative feedback regulators of BMP signaling themselves. Moreover, the BMP pathway cross-talks with mechanical cues in bone, a feature that is increasingly being recognized in the vessel wall as well [5]. However, also its interactions and cross-talk with other pathways contribute to the contextual status that regulates and fine-tunes the BMP pathway (Figure 1). Here, we provide the most relevant pathway tuning and interplay between BMP signaling and other vascular pathways. These have especially been documented in the blood vasculature and may inspire lymphatic studies of the future.
Figure 1. Overview of the different levels of BMP pathway fine-tuning. Circled numbers denote examples of levels of regulation of the signaling output. Cell–cell junctions are tight, adherence and gap junctions (details are provided in the text). Abbreviations: BMP: bone morphogenetic protein BMPER: BMP endothelial cell precursor-derived regulator; CoF: co-factors; P: Phosphorylation; ECM: extracellular matrix; Ephb2: Ephrin B2; Hey: hairy/enhancer-of-split related with YRPW motif protein; Jag: Jagged; MMP: Matrix metalloproteinases; SIP: SMAD interacting proteins; Tmem100: transmembrane protein 100; Vegf: vascular endothelial growth factor; Vegfr: VEGF receptor.

3. BMP-Linked Vascular Pathologies

Blood vasculature—The germline deletion of all vascular BMP genes, except for BMP9 (Gdf2), and BMP receptor genes in mice causes embryonic lethality, with most prominent defects in mesoderm formation and cardiovascular development. This illustrates that this pathway exerts critical functions during embryogenesis [1][2][6]. Additionally, mutations in genes encoding BMP pathway components, ranging from ligands, type I and type II receptors, co-receptors and intracellular effectors, have been associated with cardiovascular disease [1][2][3][4] (Figure 2). Indeed, human studies have shown that impaired BMP signaling causes hereditary hemorrhagic telangiectasia (HHT), pulmonary arterial hypertension (PAH), cerebral cavernous malformation (CCM), bicuspid aortic valve with thoracic aorta aneurysm (BAC/TAA) and aortic valve stenosis (AOVD2), atherosclerosis combined with vascular calcifications and fibrodysplasia ossificans progressiva (FOP). Some of these diseases, i.e., HHT, PAH, BAC and AOVD2, result from reduced BMP signaling (loss of function), whereas others such as CCM and FOP reflect a gain of function. This illustrates, again, the critical dosage of signaling of this family of morphogens.


  1. García de Vinuesa, A.; Abdelilah-Seyfried, S.; Knaus, P.; Zwijsen, A.; Bailly, S. BMP signaling in vascular biology and dysfunction. Cytokine Growth Factor Rev. 2015.
  2. Goumans, M.-J.; Zwijsen, A.; ten Dijke, P.; Bailly, S. Bone morphogenetic proteins in vascular homeostasis and disease. Cold Spring Harb. Perspect. Biol. 2018, 10.
  3. Morrell, N.W.; Bloch, D.B.; Ten Dijke, P.; Goumans, M.J.T.H.; Hata, A.; Smith, J.; Yu, P.B.; Bloch, K.D. Targeting BMP signalling in cardiovascular disease and anaemia. Nat. Rev. Cardiol. 2016, 13, 106–120.
  4. Cunha, S.I.; Magnusson, P.U.; Dejana, E.; Lampugnani, M.G. Deregulated TGF-β/BMP signaling in vascular malformations. Circ. Res. 2017, 121, 981–999.
  5. Hiepen, C.; Mendez, P.-L.; Knaus, P. It takes two to tango: Endothelial TGFβ/BMP Signaling crosstalk with mechanobiology. Cells 2020, 9, 1965.
  6. Wang, R.N.; Green, J.; Wang, Z.; Deng, Y.; Qiao, M.; Peabody, M.; Zhang, Q.; Ye, J.; Yan, Z.; Denduluri, S.; et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis. 2014, 1, 87–105.
  7. Pulkkinen, H.H.; Kiema, M.; Lappalainen, J.P.; Toropainen, A.; Beter, M.; Tirronen, A.; Holappa, L.; Niskanen, H.; Kaikkonen, M.U.; Ylä-Herttuala, S.; et al. BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF. Angiogenesis 2020, 24.
  8. Helbing, T.; Rothweiler, R.; Ketterer, E.; Goetz, L.; Heinke, J.; Grundmann, S.; Duerschmied, D.; Patterson, C.; Bode, C.; Moser, M. BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium. Blood 2011, 118, 5040–5049.
  9. Choi, E.J.; Walker, E.J.; Shen, F.; Paul Oh, S.; Arthur, H.M.; Young, W.L.; Su, H. Minimal homozygous endothelial deletion of eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. Cerebrovasc. Dis. 2012, 33, 540–547.
  10. Bernabeu, C.; Bayrak-Toydemir, P.; McDonald, J.; Letarte, M. Potential second-hits in hereditary hemorrhagic telangiectasia. J. Clin. Med. 2020, 9, 3571.
  11. Pachori, A.S.; Custer, L.; Hansen, D.; Clapp, S.; Kemppa, E.; Klingensmith, J. Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J. Mol. Cell. Cardiol. 2010, 48, 1255–1265.
  12. Nakagawa, Y.; Ikeda, K.; Akakabe, Y.; Koide, M.; Uraoka, M.; Yutaka, K.T.; Kurimoto-Nakano, R.; Takahashi, T.; Matoba, S.; Yamada, H.; et al. Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1908–1915.
  13. Morikawa, M.; Mitani, Y.; Holmborn, K.; Kato, T.; Koinuma, D.; Maruyama, J.; Vasilaki, E.; Sawada, H.; Kobayashi, M.; Ozawa, T.; et al. The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension. Sci. Signal. 2019, 12.
  14. Liu, T.; Zou, X.Z.; Huang, N.; Ge, X.Y.; Yao, M.Z.; Liu, H.; Zhang, Z.; Hu, C.P. miR-27a promotes endothelial-mesenchymal transition in hypoxia-induced pulmonary arterial hypertension by suppressing BMP signaling. Life Sci. 2019, 227, 64–73.
  15. Tian, F.; Zhou, A.X.; Smits, A.M.; Larsson, E.; Goumans, M.J.; Heldin, C.H.; Borén, J.; Akyürek, L.M. Endothelial cells are activated during hypoxia via endoglin/ALK-1/SMAD1/5 signaling in vivo and in vitro. Biochem. Biophys. Res. Commun. 2010, 392, 283–288.
Subjects: Cell Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 709
Revisions: 2 times (View History)
Update Date: 27 Jul 2021