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.
Highlights
Vascular disease, which may present with different pathological and clinical pictures, including arteriosclerosis, atherosclerosis, aortic aneurysms and vascular calcification, is a main cause of increased cardiovascular (CV) morbidity and mortality in aging and very common diseases, such as diabetes and chronic kidney disease (CKD) [1]
The negative effects of Mstn on muscle growth have been involved in the pathogenesis of age-related sarcopenia [29], as well as in cachexia associated with cancer [30], chronic kidney disease [31], and heart failure [32]
In vitro studies on vascular smooth muscle cell (VSMC) originated from the iliac artery and aorta of organ donors showed that Act-A induces the contractile, nonproliferative phenotype in cultured smooth muscle cells
Summary
Vascular disease, which may present with different pathological and clinical pictures, including arteriosclerosis, atherosclerosis, aortic aneurysms and vascular calcification, is a main cause of increased cardiovascular (CV) morbidity and mortality in aging and very common diseases, such as diabetes and chronic kidney disease (CKD) [1]. Mechanisms and mediators leading to VSMC aging include mechano-stimuli, chronic inflammation, apoptosis, epigenetic events and calcification; these factors promote aging-induced changes in the VSMC functional pattern, including the ability to contract and assemble extracellular matrix proteins This ageinduced arterial remodeling identifies arteriosclerosis and provides a major risk for the development of atherosclerosis [3]. Despite recent advances in the understanding of the biology and pathogenesis of vascular damage in several conditions, including CKD, no satisfactory therapeutic strategies have been defined, yet [4,5] This observation underlines the need to better clarify pathogenetic mechanisms of vascular disease to identify new potential therapeutic targets. Among the members of the TGF-β family, both myostatin (Mstn), a potent inhibitor of skeletal muscle development, and activin-A (Act-A), a multifunctional growth and differentiation factor, have been recently studied as potential regulators of vascular biology. The subsequent proteolytic cleavage by BMP1/Tolloid family metalloproteases releases active Mstn [11]
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