Vascular Calcification: New Insights Into BMP Type I Receptor A

Niu, Zhixing; Su, Guanyue; Li, Tiantian; Yu, Hongchi; Shen, Yang; Zhang, Demao; Liu, Xiaoheng

doi:10.3389/fphar.2022.887253

Cited by 7 publications

(5 citation statements)

References 105 publications

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“…Eosinophils or mEar1/ECP/EDN increased SMC expression of ALP, a known enzyme involved in SMC calcification. 66 The expression or functions of transcription factor osterix and transcription repressor msh homeobox-2 are also downstream targets of p-Smad-1/5/8 activation, 67 which eosinophils and mEar1/ECP/EDN may regulate.…”

Section: Discussionmentioning

confidence: 99%

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis

Meng

Zhang

et al. 2023

European Heart Journal

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Aims Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. Methods and results Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4−/−, and Il13−/− mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-β receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. Conclusion Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis

Meng

Zhang

et al. 2023

European Heart Journal

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“…The Involvement of SMAD signaling pathways via TGF family receptors in smooth muscle cell calcification has been extensively studied in the past [43,44]. While SMAD1/5/8 is classically activated via BMP2 in VSMC and leads to vascular calcification [44][45][46], SMAD2/3 has been directly linked to TGFβ activation and promotes smooth muscle cell differentiation [47,48]. Interestingly, we showed that LRG1 enhanced the activation of the TGFβ-induced SMAD1/5 signaling pathway in VSMC without affecting the SMAD2/3 axis.…”

Section: Discussionmentioning

confidence: 99%

Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification

Grzesiak,

Amaya-Garrido,

Feuillet

et al. 2023

IJMS

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Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE−/−) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis.

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“…Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily essential for development, but they also participate in the regulation of cardiovascular structure and function. The extracellular binding of BMP to type I and type II receptors leads to the formation of heteromeric signaling complexes [ 99 , 100 ]. The canonical pathway induces the phosphorylation of Smad1/5/8 (R-Smad), which binds to Smad4 and the complex translocates into the nucleus to regulate gene expression [ 101 ].…”

Section: Molecular Networking In Vascular Calcificationmentioning

confidence: 99%

Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities

Ortega,

De Leon-Oliva,

Gimeno-Longas

et al. 2024

Biomolecules

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Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO43− and ionized calcium (Ca2+). It is a crucial process in the development of bones and teeth. However, pathological calcification can occur in almost any soft tissue of the organism. The better studied is vascular calcification, where calcium salts can accumulate in the intima or medial layer or in aortic valves, and it is associated with higher mortality and cardiovascular events, including myocardial infarction, stroke, aortic and peripheral artery disease (PAD), and diabetes or chronic kidney disease (CKD), among others. The process involves an intricate interplay of different cellular components, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and pericytes, concurrent with the activation of several signaling pathways, calcium, Wnt, BMP/Smad, and Notch, and the regulation by different molecular mediators, growth factors (GFs), osteogenic factors and matrix vesicles (MVs). In the present review, we aim to explore the cellular players, molecular pathways, biomarkers, and clinical treatment strategies associated with vascular calcification to provide a current and comprehensive overview of the topic.

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Vascular Calcification: New Insights Into BMP Type I Receptor A

Cited by 7 publications

References 105 publications

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis

Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification

Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities

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