Glucose and Smooth Muscle Cells: Unraveling the Metabolic Signals Behind Vascular Calcification

In this issue of Acta Physiologica, Heuschkel et al. Present compelling evidence of the hypotaurine metabolic pathway being involved in glucose-induced vascular smooth muscle cell (SMC) calcification. Using state-of-the-art in vitro approaches, their study reveals that elevated glucose levels in SMCs promote extracellular matrix calcification, suggesting potential novel therapeutic targets for hyperglycemia-driven vascular disease [1].

With the global rise in type 2 diabetes (T2D) and accompanying macrovascular complications, manifestations of atherosclerosis and arterial stiffening pose major clinical challenges. Vessels of diabetic patients present increased intimal and medial calcification, which has been associated with cardiovascular events and poor outcomes [2]. It has been hypothesized that prevention or halted calcification can improve clinical outcomes in diabetic populations.

Vascular calcification is an active process that involves many factors such as metabolic changes, oxidative stress, inflammation, and cellular trans-differentiation. In individuals with T2D, chronic hyperglycemia accelerates this process by promoting the production of advanced glycosylation end-products, endothelial dysfunction and immune cell infiltration, creating a microenvironment that favors the osteochondrogenic transformation of SMCs within the vessel wall [3]. However, despite decades of research, no pharmacological therapy has been approved to prevent or reverse vascular calcification. One major challenge lies in the overlap between many of the key molecular pathways involved in vascular calcification and those in bone metabolism, posing difficulties in targeting either of them without systemic side effects. Furthermore, the vast complexity of calcification, including different types such as macro- and micro-calcification, different stages during the progression of calcification formation, and the fact that it is usually detected at an advanced irreversible stage, all indicate that it cannot be targeted uniformly. To date, no safe, specific, and effective pharmacological treatment has been validated in clinical trials, underscoring an urgent need for novel research strategies and targets in this field.

In this study, Heuschkel et al. investigate the SMC-related metabolic changes that result in calcification under hyperglycemic conditions. In the search for novel pathways and targets, they employ a multi-omics approach integrating transcriptomic and metabolomic data derived from in vitro glucose-induced calcifying SMCs. As expected, high glucose promoted calcification of SMCs. However, this was not accompanied by the upregulation of classical osteochondrogenic markers such as ALPL, RUNX2, BMP2, and SOX9, suggesting the involvement of alternative mechanisms. Through integrated analysis of transcriptomic and intra- and extra-cellular metabolomic data, the authors identified the hypotaurine metabolic pathway as a novel contributor to glucose-induced SMC calcification. Their multi-omics approach emphasizes the importance of the extracellular metabolome as a valuable source for uncovering new targets in vascular calcification. This aligns with emerging evidence that alterations in extracellular mineral metabolism, such as disrupted pyrophosphate homeostasis, can exacerbate calcification in hyperglycemic conditions [4]. One specific methodological point related to this study is that the authors focus on early time points of the calcification process. The rationale for identifying molecular pathways and targets for the prevention of vascular calcification at an early time point is important due to the difficulty of treating established calcification nodes. Functional assays further revealed that inhibition of hypotaurine production increased SMC calcification, suggesting a protective role. Moreover, loss of hypotaurine transporters exacerbated calcification both in vitro and in a warfarin-induced in vivo calcification model, where reduced transporter expression was observed in the vessel wall.

While this study sheds valuable light on a novel pathway associated with glucose-induced calcification, it should be noted that the findings are primarily based on in vitro experiments using primary human SMCs. As with any in vitro model, the choice of experimental conditions, including the use of CaP-based calcification assays and time points, can influence the observed outcomes. Future research should aim to validate these findings using alternative calcification protocols and longer exposure time points, such as inorganic phosphate (Pi)-based models, all of which are commonly used in the field. Moreover, further investigation in human vascular tissues and proof of concept, interventional in vivo studies, would be essential to confirm the clinical relevance of the hypotaurine pathway and its therapeutic potential.

Together, the findings by Heuschkel and colleagues provide important evidence for a previously unrecognized metabolic pathway involved in vascular calcification via SMCs. Their study also underscores the potential of targeting early metabolic alterations in hyperglycemia-related cardiovascular disease.

The authors declare no conflicts of interest.