Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Abstract

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT

“…CACS has been reported as a non-invasive and reliable predictive tool for coronary artery calcification and CVD [6,7,37,38]. Previous studies have revealed that activin is closely related to vascular calcification [19]. Moreover, Agapova et al revealed that inhibiting the activin pathway protected against vascular calcification [31,39].…”

“…In KT patients, previous studies have reported an increase in activin levels in allografts during ischemia-reperfusion injury and alternate macrophage activation (M2 phenotype) [17,18]. Furthermore, various studies have revealed the association of activin with inflammation, vascular calcification, and carotid intima-media thickness [19,20]. Hence, studies to improve anemia, bone mineral density, and abdominal aortic vascular calcification by inhibiting the activin pathway are in progress [21][22][23].…”

Serum levels of Activin A: Marker of insulin resistance and cardiovascular risk in prediabetics

“…Esposito P et al . [ 20 ] reviewed the role of activin A in atherosclerosis and vascular disease, suggesting rationale for promising therapeutic strategies targeting this pathway.…”

Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling

“…The TGF-β superfamily features more than 30 ligands, which together regulate a great variety of developmental and homeostatic processes in all major organs including the vasculature ( 8 ). Indeed, dysregulation of TGF-β superfamily signaling has been implicated in numerous cardiomyopathies and vasculopathies, including atherosclerosis, vascular calcification, Marfan syndrome, Loeys-Dietz syndrome, and hereditary hemorrhagic telangiectasia, in addition to PAH ( 9 – 12 ). Typically, binding of a dimeric TGF-β superfamily ligand promotes assembly of a heterotetrameric signaling complex comprising two type I and two type II receptor serine/threonine kinases.…”

“…Notably, GDF11 can signal through the type I receptor ALK5, better known as the principal SMAD2/3-activating receptor used by TGF-β ( 71 , 72 ), providing a potential mechanism for convergence of GDF11- and TGF-β-mediated signals. Given emerging evidence of GDF8 involvement in vascular dysfunction and chronic inflammatory disease ( 11 , 12 , 73 , 74 ), it will be important in future studies to dissect the pathogenic contributions made specifically by GDF8, if any, to vascular remodeling in PAH. Whether any of the activin-class ligands drive pathologic vascular remodeling processes through non-canonical signaling mechanisms has not yet been investigated to our knowledge.…”