The role of BMPs in endothelial cell function and dysfunction

doi:10.1016/j.tem.2014.05.003

Trends in Endocrinology & Metabolism

Volume 25, Issue 9, September 2014, Pages 472-480

https://doi.org/10.1016/j.tem.2014.05.003 Get rights and content

Highlights

•
In addition to BMP2 and BMP4, BMP9 plays crucial, context-specific roles in the endothelium.
•
The recently coined ‘type III’ coreceptors interact with the type I and type II receptors and typically lead to endocytotic recycling of the BMP/BMP receptor complex.
•
BMPs activate different intracellular signaling cascades that play key roles in hypertension, vascular disorders, and atherosclerosis.

The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. In embryonic development, BMPs promote endothelial specification and subsequent venous differentiation. The BMP pathway also plays important roles in the adult vascular endothelium, promoting angiogenesis and mediating shear and oxidative stress. The canonical BMP pathway functions through the Smad transcription factors; however, other intracellular signaling cascades can be activated, and receptor complexes beyond the traditional type I and type II receptors add additional layers of regulation. Dysregulated BMP signaling has been linked to vascular diseases including pulmonary hypertension and atherosclerosis. This review addresses recent advances in the roles of BMP signaling in the endothelium and how BMPs affect endothelial dysfunction and human disease.

Section snippets

BMPs in endothelial cells

The importance of the BMP (see Glossary) pathway in vascular development has been known for years. Beyond its importance in embryonic development, crucial roles have been identified in vascular disorders including hereditary hemorrhagic telangiectasia (HHT) and peripheral arterial hypertension (PAH) [1]. However, during development the BMP pathway has functions beyond those in endothelial differentiation, venous specification, and angiogenesis [2]. Recent studies have shown that the BMP pathway

The role of BMP signaling during angiogenesis

BMPs typically promote angiogenesis by increasing and inducing endothelial motility and invasion and by promoting proliferation [2]. HUVECs express the BMP receptors BMPRII and BMPR1b at high levels, and treating HUVECs with exogenous BMP2 increases their motility and invasion [20]. Although BAECs show decreased apoptosis in response to BMP2 treatment [32], HUVECs do not show changes in apoptosis in response to BMP2 [20]. These differential responses may be explained by endothelial

The interaction between BMP signaling and oxygen in angiogenesis

Hypoxia is a major inducer of angiogenesis, and the BMP pathway mediates the endothelial response to low oxygen levels. BMP9 downregulates apelin via BMPRII and the R-Smad intracellular pathways in microvascular endothelial cells exposed to hypoxia [43]. This downregulation blocks apelin-induced endothelial proliferation and allows hypoxia-induced angiogenesis [43]. Upstream of the BMP ligands, BMPER is downregulated in response to hypoxia, and this relieves the BMPER-induced downregulation of

The role of BMP signaling in hypertension

Hypertension is the leading chronic risk factor for mortality, and despite significant efforts to control the mortality associated with hypertension, the prevalence is increasing in the USA [48]. Multiple BMP ligands have well-established roles in pulmonary hypertension, and BMP receptor mutations also affect the response to oxidative stress. BMP2/4 normally stimulate BMPRII to promote the phosphorylation and activity of endothelial nitric oxide synthase (eNOS) via protein kinase A activation,

Concluding remarks

As one of the major signaling pathways in endothelial cells, the BMP pathway is understandably complex, as highlighted by the number of ligands, the diversity of receptors, and the myriad functions and intracellular cascades that it affects. This intricate pathway is essential for endothelial homeostasis and responding to both normal stressors (e.g., laminar shear and oxidative stress) and abnormal stressors (e.g., inflammation, hypoxia, and hypertension). The BMP pathway has been implicated in

Acknowledgments

We would like to thank Andrea Portbury and Davin Townley-Tilson for critical reading of the manuscript and the National Institutes of Health (grant R01HL061656) for funding support.

Glossary

Angiogenesis: the process of generating new blood vessels from existing blood vessels; requires endothelial proliferation, sprouting and migration from existing vessels, and tube formation in the next destination.
BAECs: bovine arterial endothelial cells.
Bone morphogenetic protein (BMP): one of the two major subfamilies of the TGF-β superfamily; regulatory growth factor.
BMP receptors (BMPRs): a family of transmembrane serine/threonine kinases that include type I (BMPR1A) and type II receptors (BMPR1B,

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Bone morphogenetic protein 9 (BMP9) has been validated as one of the most potent osteoinduction factors, but its underlying mechanism remains unclear. As a member of the matrix metalloproteinase (MMP) family, MMP13 may be involved in regulating the lineage-specific differentiation of mouse embryonic fibroblasts (MEFs). The goal of this study was to determine whether MMP13 regulates the osteoinduction potential of BMP9 in MEFs, which are multipotent progenitor cells widely used for stem cell biology research. In vitro and in vivo experiments showed that BMP9-induced osteogenic markers and/or bone were enhanced by exogenous MMP13 in MEFs, but were reduced by MMP13 knockdown or inhibition. The expression of hypoxia inducible factor 1 alpha (HIF-1α) was induced by BMP9, which was enhanced by MMP13. The protein expression of β-catenin and phosphorylation level of glycogen synthase kinase-3 beta (GSK-3β) were increased by BMP9 in MEFs, as was the translocation of β-catenin from the cytoplasm to the nucleus; all these effects of BMP9 were enhanced by MMP13. Furthermore, the MMP13 effects of increasing BMP9-induced β-catenin protein expression and GSK-3β phosphorylation level were partially reversed by HIF-1α knockdown. These results suggest that MMP13 can enhance the osteoinduction potential of BMP9, which may be mediated, at least in part, through the HIF-1α/β-catenin axis. Our findings demonstrate a novel role of MMP13 in the lineage decision of progenitor cells and provide a promising strategy to speed up bone regeneration.
H3K27me3-modulated Hofbauer cell BMP2 signalling enhancement compensates for shallow trophoblast invasion in preeclampsia
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Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown to promote trophoblast invasion in vitro, its cellular origin and molecular regulation in placenta, as well as its potential role in PE, has yet to be established. Additionally, whether BMP2 and/or its downstream molecules could serve as potential diagnostic or therapeutic targets for PE has not been explored.
Placentas and sera from PE and healthy pregnant women were subjected to multi-omics analyses, immunoblots, qPCR, and ELISA assays. Immortalized trophoblast cells, primary cultures of human trophoblasts, and first-trimester villous explants were used for in vitro experiments. Adenovirus expressing sFlt-1 (Ad Flt1)-induced PE rat model was used for in vivo studies.
We find globally decreased H3K27me3 modifications and increased BMP2 signalling in preeclamptic placentas, which is negatively correlated with clinical manifestations. BMP2 is derived from Hofbauer cells and epigenetically regulated by H3K27me3 modification. BMP2 promotes trophoblast invasion and vascular mimicry by upregulating BMP6 via BMPR1A-SMAD2/3-SMAD4 signalling. BMP2 supplementation alleviates high blood pressure and fetal growth restriction phenotypes in Ad Flt1-induced rat PE model.
Our findings demonstrate that epigenetically regulated Hofbauer cell-derived BMP2 signalling enhancement in late gestation could serve as a compensatory response for shallow trophoblast invasion in PE, suggesting opportunities for diagnostic marker and therapeutic target applications in PE clinical management.
National Key Research and Development Program of China (2022YFC2702400), National Natural Science Foundation of China (82101784, 82171648, 31988101), and Natural Science Foundation of Shandong Province (ZR2020QH051, ZR2020MH039).
The role of endothelial cell in cardiac hypertrophy: Focusing on angiogenesis and intercellular crosstalk
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Cardiac hypertrophy is characterized by cardiac structural remodeling, fibrosis, microvascular rarefaction, and chronic inflammation. The heart is structurally organized by different cell types, including cardiomyocytes, fibroblasts, endothelial cells, and immune cells. These cells highly interact with each other by a number of paracrine or autocrine factors. Cell-cell communication is indispensable for cardiac development, but also plays a vital role in regulating cardiac response to damage. Although cardiomyocytes and fibroblasts are deemed as key regulators of hypertrophic stimulation, other cells, including endothelial cells, also exert important effects on cardiac hypertrophy. More particularly, endothelial cells are the most abundant cells in the heart, which make up the basic structure of blood vessels and are widespread around other cells in the heart, implicating the great and inbuilt advantage of intercellular crosstalk. Cardiac microvascular plexuses are essential for transport of liquids, nutrients, molecules and cells within the heart. Meanwhile, endothelial cell-mediated paracrine signals have multiple positive or negative influences on cardiac hypertrophy. However, a comprehensive discussion of these influences and consequences is required. This review aims to summarize the basic function of endothelial cells in angiogenesis, with an emphasis on angiogenic molecules under hypertrophic conditions. The secondary objective of the research is to fully discuss the key molecules involved in the intercellular crosstalk and the endothelial cell-mediated protective or detrimental effects on other cardiac cells. This review provides a more comprehensive understanding of the overall role of endothelial cells in cardiac hypertrophy and guides the therapeutic approaches and drug development of cardiac hypertrophy.
The impact of gender and peripheral blood parameters on the characteristics of L-PRF membranes
2022, Journal of Oral Biology and Craniofacial Research
The purpose of this study was to evaluate the impact of gender and peripheral blood parameters on the characteristics of Leucocyte-and Platelet-Rich Fibrin (L-PRF) membranes and to describe histologically three different zones of L-PRF membranes.
Blood was collected from twenty healthy donors (10 men and 10 women). Peripheral blood parameters including leucocyte and platelet counts, and fibrinogen levels were recorded. L-PRF membranes were prepared to quantify the release of growth factors (PDGF, VEGF, BMP-2, and BMP-9) at 1, 2, 3 and 7 days and for histological examination. Three zones within each L-PRF membrane (face, body, and tail) were analysed separately, quantifying the area of leucocytes, platelets, and fibrin in percentage. The Young's modulus of the membranes was also considered (during tensile and compression tests).
Women had significantly higher fibrinogen levels in their peripheral blood, and a higher release of BMP-9, whereas men showed a significantly higher Young's modulus in compression tests. The histology revealed significant differences in cellular content and fibrin concentration between the 3 areas, with the face being biologically the richest.
Several factors influenced the final characteristics of L-PRF membranes. These need to be taken into consideration when interpreting the results of research, but especially in clinical practice.
Two-stage degradation and novel functional endothelium characteristics of a 3-D printed bioresorbable scaffold
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MGF is an isomer of insulin-like growth factor 1 (IGF-1) that can respond to pressure, injury, and disease [53,54]. BMP family members play important roles in bone repair by rapidly up-regulating the levels of endogenous BMP2 and phosphorylated Smad, and these proteins are responsive to mechanical signals [55]. In addition, MGF can promote BMP2 expression, as was shown in a previous study of bone repair [56].
Bioresorbable scaffolds have emerged as a new generation of vascular implants for the treatment of atherosclerosis, and designed to provide a temporary scaffold that is subsequently absorbed by blood vessels over time. Presently, there is insufficient data on the biological and mechanical responses of blood vessels accompanied by bioresorbable scaffolds (BRS) degradation. Therefore, it is necessary to investigate the inflexion point of degradation, the response of blood vessels, and the pathophysiological process of vascular, as results of such studies will be of great value for the design of next generation of BRS. In this study, abdominal aortas of SD rats were received 3-D printed poly-l-actide vascular scaffolds (PLS) for various durations up to 12 months. The response of PLS implanted aorta went through two distinct processes: (1) the neointima with desirable barrier function was obtained in 1 month, accompanied with slow degradation, inflammation, and intimal hyperplasia; (2) significant degradation occurred from 6 months, accompanied with decreasing inflammation and intimal hyperplasia, while the extracellular matrix recovered to normal vessels which indicate the positive remodeling. These in vivo results indicate that 6 months is a key turning point. This “two-stage degradation and vascular characteristics” is proposed to elucidate the long-term effects of PLS on vascular repair and demonstrated the potential of PLS in promoting endothelium function and positive remodeling, which highlights the benefits of PLS and shed some light in the future researches, such as drug combination coatings design.
MiR-340-5p inhibits Müller cell activation and pro-inflammatory cytokine production by targeting BMP4 in experimental diabetic retinopathy
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Citation Excerpt :
In recent years, BMPs have been reported to exert biological functions in the pathophysiology of DR or DR-related diseases [17]. BMPs promote endothelial motility and invasion to facilitate angiogenesis [17]. Based on the structural homology, BMPs are divided into numerous subgroups, including BMP2/4, BMP5/6/7/8, BMP9/10 and BMP12/13/14 [18].
Diabetic retinopathy (DR) is a disease that can cause blindness. Bone morphogenetic protein-4 (BMP4) was reported be overexpressed in DR model. However, the specific mechanism of BMP4 in DR development has not been explored. MiR-340-5p and BMP4 levels were detected by RT-qPCR in MIO‐M1 cells and retinas of mice. Western blot analysis was used to examine GFAP, BMP4 and BRB junction protein levels. Inflammatory cytokine secretion and the retina structure were examined by ELISA and H&E staining, respectively. The interaction between miR-340-5p and BMP4 was identified by luciferase reporter assay. In HG-stimulated MIO‐M1 cells, BMP4 was upregulated. Mechanically, BMP4 was targeted by miR-340-5p and negatively regulated by miR-340-5p. In rescue assays, BMP4 countervailed the suppressive effects of miR-340-5p on activation of Müller cells and release of inflammatory cytokines. Additionally, miR-18a-3p overexpression alleviated BRB injury to inhibit DR progression in vivo. In conclusion, miR-340-5p inhibits DR progression by targeting BMP4, which may offer a new pathway for treatment of DR.

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Trends in Endocrinology & Metabolism

ReviewThe role of BMPs in endothelial cell function and dysfunction

Highlights

Section snippets

BMPs in endothelial cells

The role of BMP signaling during angiogenesis

The interaction between BMP signaling and oxygen in angiogenesis

The role of BMP signaling in hypertension

Concluding remarks

Acknowledgments

Glossary

FEBS Lett.

Semin. Cell Dev. Biol.

Biochem. Pharmacol.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

Microvasc. Res.

J. Mol. Cell Cardiol.

J. Biol. Chem.

J. Mol. Cell Cardiol.

Dev. Cell

J. Biol. Chem.

Blood

Dev. Cell

Dev. Cell

Blood

Biochem. Biophys. Res. Commun.

Blood

J. Biol. Chem.

Microvasc. Res.

J. Thromb. Haemost.

Curr. Opin. Cell Biol.

Blood

J. Biol. Chem.

EndMT contributes to the onset and progression of cerebral cavernous malformations

Nature

Sequential roles for myosin-X in BMP6-dependent filopodial extension, migration, and activation of BMP receptors

J. Cell Biol.

Bone morphogenetic proteins protect pulmonary microvascular endothelial cells from apoptosis by upregulating alpha-B-crystallin

Arterioscler. Thromb. Vasc. Biol.

Heat shock protein 70 enhances vascular bone morphogenetic protein-4 signaling by binding matrix Gla protein

Circ. Res.

Matrix Gla protein deficiency causes arteriovenous malformations in mice

J. Clin. Invest.

BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo

J. Cell Sci.

Controlling angiogenesis by two unique TGF-beta type I receptor signaling pathways

Histol. Histopathol.

Bone morphogenetic protein-9 is a circulating vascular quiescence factor

Circ. Res.

BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis

J. Cell Sci.

Review
The role of BMPs in endothelial cell function and dysfunction