The context-dependent role of transforming growth factor-β/miR-378a-3p/connective tissue growth factor in vascular calcification: a translational study

Abstract

Background: Vascular calcification (VC) constitutes an important vascular pathology with prognostic importance. The pathogenic role of transforming growth factor-β (TGF-β) in VC remains unclear, with heterogeneous findings that we aimed to evaluate using experimental models and clinical specimens. Methods: Two approaches, exogenous administration and endogenous expression upon osteogenic media (OM) exposure, were adopted. Aortic smooth muscle cells (ASMCs) were subjected to TGF-β1 alone, OM alone, or both, with calcification severity determined. We evaluated miR-378a-3p and TGF-β1 effectors (connective tissue growth factor; CTGF) at different periods of calcification. Results were validated in an ex vivo model and further in sera from older adults without or with severe aortic arch calcification. Results: TGF-β1 treatment induced a significant dose-responsive increase in ASMC calcification without or with OM at the mature but not early or mid-term VC period. On the other hand, OM alone induced VC accompanied by suppressed TGF-β1 expressions over time; this phenomenon paralleled the declining miR-378a-3p and CTGF expressions since early VC. TGF-β1 treatment led to an upregulation of CTGF since early VC but not miR-378a-3p until mid-term VC, while miR-378a-3p overexpression suppressed CTGF expressions without altering TGF-β1 levels. The OM-induced down-regulation of TGF-β1 and CTGF was also observed in the ex vivo models, with compatible results identified from human sera. Conclusions: We showed that TGF-β1 played a context-dependent role in VC, involving a time-dependent selfregulatory loop of TGF-β1/miR-378a-3p/CTGF signaling. Our findings may assist subsequent studies in devising potential therapeutics against VC.

Vascular Calcification Heterogeneity from Bench to Bedside: Implications for Manifestations, Pathogenesis, and Treatment Considerations

“…Fluctuations in the agonistic and antagonistic activities of pathogenic VC signaling serve as an alternative impetus for inducing VC heterogeneity. In addition, our group recently discovered that procalcific stimuli may be mutually antagonistic; using in vitro and ex vivo models, we demonstrated that exogenous TGFβ administration intensified VC severity, whereas other pro-calcific factors triggered a downregulation of endogenous TGFβ expressions [48]. These findings further imply that the primary drivers of VC determine the predominant pathway(s) leading to calcification, and that VC subtyping, as well as the selection of individual druggable targets, can be a potential therapeutic option.…”

“…However, a meta-analysis of 29 observational studies and 12 randomized trials concluded that statin use did not significantly attenuate coronary calcification [85], while another suggested that statins may aggravate coronary calcification [86]. Elevated inorganic phosphate levels have been shown to induce experimental VC [48,87]; however, phosphate reduction does not consistently reduce VC severity in at-risk populations [88]. These historical examples illustrate failed attempts to pursue a homogenous treatment strategy for VC and point toward a more rational approach by advancing our understanding of VC heterogeneity.…”

Profibrotic role of transcription factor SP1 in cross-talk between fibroblasts and M2 macrophages

“… 10 However, some studies have shown that TGF-β1 has an inhibitory effect on the activity of fibroblasts. 11 , 12 Contradictory data may reflect the context-dependent role of TGF-β1. M2 macrophages may produce a large amount of latent TGF-β1 in fibrosis.…”