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    Topic review

    Bone Morphogenetic Proteins

    Subjects: Cell Biology
    View times: 4
    Submitted by: Ljuba Ponomarev

    Definition

    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.

    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.

    The entry is from 10.3390/ijms22126364

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