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Volume 16, Issue 1

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Magnesium alloys for vascular stents: the biological bases

A focus on the effects of magnesium on vascular cells

Sara Castiglioni
  • Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via G.B. Grassi 74, Milano I-20157, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jeanette A.M. Maier
  • Corresponding author
  • Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via G.B. Grassi 74, Milano I-20157, Italy
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-06-05 | DOI: https://doi.org/10.1515/bnm-2015-0003

Abstract

Bioabsorbable vascular stents in magnesium alloys provide an attractive alternative to standard stainless steel metal stents, because of their adequate radial force, high biocompatibility, low thrombogenicity and intrinsic dissolution in body fluids. Since magnesium is the major component of the alloys, high concentrations of this element can be achieved in the local microenvironment as a results of corrosion. Magnesium is known to grant cardiovascular protection and to be beneficial for the cells of the vascular wall. This review summarizes present knowledge about the effects of high magnesium levels on smooth muscle and endothelial cells.

Keywords: endothelial cells; magnesium; smooth muscle cells

Introduction

The advent of stents has opened a new era in treating ischemia due to atherosclerotic arterial disease. Indeed, stents are widely used to improve blood supply to the tissues. The ideal stent, in addition to possessing an adequate radial force, should be biocompatible and normalize vascular function. Permanent bare metal stents often promote an arterial response that leads to restenosis. Drug-eluting stents have then been developed. They release anti-proliferative drugs to prevent the growth of scar tissue in the lumen. They significantly reduce restenosis but are associated with hypersensitive reactions mediated by eosinophils and late thrombosis [1]. Because they are rigid, metallic stents impact on blood flow, vasomotion and remodeling, and might alter endothelial function [2]. Furthermore, metal stents can hinder the visualization of the vessels as detected by non-invasive imaging techniques such as computer tomography or magnetic resonance [3]. In addition, the presence of permanently caged vessel segments complicates eventual re-intervention on the lesion.

Metallic bioabsorbable scaffolds could represent a valid alternative to conventional stents. It is mandatory that they provide structural support for a time long enough (approx. 10–12 months) to permit the healing of the vessel wall, before beginning degradation to allow the normalization of vascular functions and restore flow dynamics. Therefore, biodegradable metals should perform similarly to the metals used for permanent stents, be biocompatible and beneficial for the healing process. In addition, degradation should occur without embolization and the consequent loss of strength must be predictable. It is noteworthy that bioabsorbable polymer-drug-eluting stents have been designed. They are superior to first generation durable polymer drug eluting stents but inferior to second-generation durable polymer stents for long term safety [4]. Recently, a large scale network meta-analysis has reported that biodegradable polymer-biolimus eluting stents are associated with better outcomes than bare-metal stents and with similar clinical outcomes if compared with second-generation durable polymer-drug eluting stents [5].

Magnesium (Mg) alloys fulfill most of the aforementioned requirements and are particularly attractive since Mg is an essential element involved in many crucial processes.

A rapid overview on magnesium

Total Mg in adults is nearly 25 g, with 50%–60% stored in the bone and only 1% in the extracellular milieu [6]. Its homeostasis is strictly regulated through an interplay between the intestine and the kidneys. Intestinal absorption occurs by passive paracellular mechanisms and by the intervention of specific transporters belonging to the transient receptor potential channel family, i.e. TRPM6 and 7 [7]. It is noteworthy that absorption in the gut is dependent on individual Mg status. In the kidney, filtered Mg is reabsorbed through a paracellular pathway mainly in the thick ascending limb, while 5%–10% of Mg is reabsorbed in the distal convoluted tubule by tightly regulated active transcellular transport mediated by TRPM6 [8]. The distal tubule ultimately regulates urinary secretion of Mg. The kidney can increase the fractional excretion of Mg to nearly 100% when its renal threshold is exceeded. Consequently, redundant Mg is secreted and no overload occurs unless chronic kidney disease occurs.

Magnesium is primarily within the cells where it represents the second most prevalent cation. It is integral to the function of ATP and involved in the regulation of hundreds of enzymatic reactions, participating to the metabolism of carbohydrates, lipids, proteins and nucleic acids [9]. It maintains genomic stability, it is an essential contributor to RNA tertiary structure, it also plays a role in the control of transcription and translation. It interacts with phospholipids thus impacting on membrane fluidity and permeability. Moreover, Mg2+ regulates the activity of some ion channels and modulates transmembrane transport of calcium, potassium and sodium.

Magnesium-based biodegradable stents

Mg is rapidly corroded and its mechanical strength is insufficient. To overcome these limitations, Mg has been alloyed with other metals and, indeed, resistance to corrosion and mechanical properties were markedly improved [10]. After their successful implantation in animals with the demonstration of good biocompatibility, prototypes of biodegradable Mg stent have been used to treat critical lower limb ischemia in adult patients [11]. No allergic or toxic reactions were reported but the long-term efficacy was similar to standard angioplasty.

The first success came from the implantation of a stent in a preterm baby born at 26 weeks of gestation with an occlusion of the left pulmonary artery [12]. No restenosis or neointima formation were detected. In the BioSolve-I trial Mg stent in the coronary arteries showed an excellent safety with no restenosis and good clinical and angiographic performances up to 12 months of follow up [13]. Interestingly, in the stent-treated fragment vascular reactivity was restored. While there are some issues that deserve further consideration, the outcome of this study is promising. Bioabsorbable Mg scaffold might revolutionize the field of coronary intervention. Indeed, there is a rational in the use of Mg stent in the vessels, since this metal is beneficial for the vascular tree. Accordingly, Mg deficiency is linked to atherosclerosis [14] and its supplementation reduces carotid intima-media thickening and ameliorates endothelial function [15, 16].

Magnesium and the endothelial cells

The endothelial cells, which form the inner lining of the vasculature, are key regulators of vascular homeostasis since they are responsible for essential secretory, synthetic, metabolic and immunologic activities [17]. Indeed, apart from representing a selective permeability barrier, the endothelium reacts to chemical and physical stimuli, regulates hemostasis, vasomotor tone, immune and inflammatory responses and produces extracellular matrix (ECM) components. Moreover, a functional relation exists between endothelial and smooth muscle cells, as a consequence of endothelial release of vasoactive mediators, growth factors and inhibitors [17]. On these bases, it is not surprising that endothelial activation or dysfunction is an early finding in the development of cardiovascular diseases and has a role in the onset of clinical events in patients with hypertension or atherosclerosis [18].

Among others, low concentrations of Mg activate cultured endothelial cells and promote the acquisition of a pro-inflammatory, pro-atherogenic phenotype [14, 19]. These effects are reversible, since, after culture in low Mg, its re-addition to the medium to reach the physiologic concentration restores the physiologic activities of endothelial cells [20]. Accordingly, Mg supplementation is beneficial in patients with coronary artery disease [16]. Since a 2-fold increase in Mg concentration has been measured in the vessel wall after the implantation of Mg-based alloy in pigs [21], it is relevant to get insights into the response of endothelial cells to concentration of Mg higher that the physiological one, i.e. ∼1.0 mM. Our present knowledge derives from studies on cultured endothelial cells, which are known to represent a valuable preclinical model to decipher molecular circuitry and identify molecules useful to prevent or treat endothelial dysfunction. Because vascular endothelium is structurally and functionally heterogeneous [22], it is noteworthy that this review will focus on studies performed on human macrovascular endothelial cells.

Intracellular Mg homeostasis

Magnesium homeostasis in eukaryotic cells is tightly controlled by mechanisms acting on its influx and efflux across the plasma membrane, and on intracellular buffering and compartmentalization. At the moment, the only transporter described in endothelial cells is TRPM7 [23, 24], an ubiquitously expressed divalent cation channel with the unique characteristics of being an ion channel and a kinase [25]. On the contrary, the exchangers involved in Mg extrusion have not been defined at the molecular level. In endothelial cells, the basal intracellular Mg content is slightly affected by low or high (up to 10 mM) concentrations of extracellular Mg [21, 26], partly because of the regulation of TRPM7 levels. Indeed, high extracellular Mg decreases the levels of TRPM7, while low extracellular Mg stimulates TRPM7 accumulation [23].

High Mg, proliferation and migration

Some studies have been performed on human macrovascular endothelial cells exposed to concentrations of extracellular Mg between 1 and 10 mM [10, 21, 27, 28]. Within this range the cells are viable, while concentrations of Mg higher than 20 mM reduce cell viability, partly through osmolality stress partly through an ionic imbalance that might alter signal transduction [10]. Human endothelial cells derived from the umbilical vein and the coronary arteries are growth stimulated when cultured in high Mg [21, 27]. This enhanced proliferation does not correlate with significant changes in RNA abundance and is partially mediated by the regulation of energy production and the stimulation of the activity of enzymes requiring Mg to function. To this purpose it is noteworthy that Mg is a cofactor for DNA polymerases and other enzymes necessary for DNA duplication [9].

Also cell migration, a crucial event in endothelialization, is enhanced in endothelial cells exposed to high Mg [10, 27]. Several mechanisms can be envisioned. Apart from inducing integrin function, Mg is needed for the assembly of actin polymers and for myosin ATPase activity, two crucial components of the motor responsible for cell migration. In addition, coordinated actions of protein tyrosine kinases and phosphatases (PTP) are instrumental for motility. High Mg inhibits endothelial migration also by down-regulating the tyrosine phosphatase HD-PTP (PTPN23) [29], since HD-PTP inhibition stimulates endothelial motility [30].

It is also possible that high extracellular Mg induces the growth and migration of macrovascular endothelial cell by down-regulating TRPM7 [23], because TRPM7 inhibition enhances these phenomena [23, 24]. This behavior is unique for macrovascular endothelial cells since silencing TRPM7 impairs the viability of all the other cell types studied, both normal and neoplastic [31].

Recently, endothelial cells were cultured on novel Mg alloys containing rare earth elements [32]. These alloys sustained cell attachment, spreading and growth, and therefore possess promising features for cardiovascular stent application.

High Mg and inflammation

Low Mg promotes inflammation [19, 33, 34], which is an important pathogenic contributor to many common diseases, from atherosclerosis to diabetes and cancer. The inflammatory response is orchestrated by the transcription factor NFkB. Under normal condition, NFkB subunits are sequestered in the cytosol because of their association with inhibitory proteins denominated IkB [35]. The classic pathway of NFkB activation determines the rapid degradation of IkB by the proteasome, the release of NFkB subunits, their nuclear translocation and binding to target genes. In endothelial cells, high Mg suppresses the inflammatory response induced by endotoxin because it protects cytosolic IkB from degradation thus preventing NFkB translocation to the nucleus [36]. Since i) oxidative stress activates NFkB, and ii) Mg has anti-oxidant properties, it is possible that high concentrations of this metal might limit the activation of the inflammatory cascade also by decreasing the production of free radicals [19]. The important issue is that inhibiting NFkB activation leads to a decreased synthesis of inflammatory mediators, adhesion molecules and cytokines [19]. All these molecules are involved in atherogenesis and thrombosis and some of them also promote smooth muscle cell proliferation and migration, thus facilitating stenosis.

Therefore, high Mg favorably impacts on endothelial function by inhibiting the NFkB pathway directly or by controlling the redox balance.

High Mg and the production of vasoactive molecules

As mentioned earlier, endothelial cells release vasoactive molecules. Nitric oxide (NO) is particularly important, since an adequate production of NO is a marker of endothelial function. Accordingly, in clinics the examination of vasodilatation in response to stimuli that release NO is routinely employed to assess endothelial function [37]. NO stimulate smooth muscle cells guanylyl cyclase to produce 3′,5′-cyclic monophosphate which causes relaxation of the blood vessels [38]. Moreover, NO limits platelet activation, adhesion and aggregation [38], important events in preventing stent thrombosis. High Mg stimulates the synthesis and release of NO and this is due to the induction of endothelial nitric oxide synthase (eNOS) [10, 27]. This finding offers a partial explanation about the reason why i) infusion of Mg lowers blood pressure [39] and ii) eNOS eluting stents result in a better re-endothelialization and in a marked reduction of neointima formation [40]. High Mg also promotes basal and vasoactive agents-stimulated prostacyclin production by vascular endothelial cells [41]. Similarly to NO, prostacyclin relaxes blood vessels and inhibits platelet activation [42]. Endothelial cells also produce endothelin-1 (ET), a potent vasoconstrictor peptide, endowed with pro-inflammatory actions, mitogenic effects, and involved in platelet activation [43]. Moreover, ET stimulates smooth muscle cell migration. Not surprisingly, therefore, ET is implicated in the development of vascular dysfunction and cardiovascular disease. To our knowledge there are no studies on the effects of high extracellular Mg on ET production in cultured endothelial cells. However, Mg supplementation reverses ET-induced vasoconstriction in different vascular beds [44] and reduces the levels of ET in various experimental models and in humans [45].

High Mg and hemostatic balance

The endothelium is fundamental in providing the proper hemostatic balance. While low Mg induces endothelial cells to acquire a pro-thrombotic phenotype [20], high extracellular Mg ensures the maintenance of blood fluidity by the means of different anti-coagulant and anti-platelet mechanisms. In response to ischemia or inflammatory stimuli, endothelial cells recruit platelets by secreting the largest multimers of von Willebrand Factor (vWF) [46]. High Mg reduces the secretion of ultra-large vWF and up-regulates its cleavage by the plasma metalloprotease ADAMTS-13 [47]. Moreover it should be recalled that Mg induces the production of NO and prostacyclin by the endothelium, thus reinforcing its relevance in inhibiting platelet adhesion, activation and aggregation. Turning our attention to platelets, it is important to point that Mg inhibits aggregation and ATP release in platelets in a dose dependent fashion, partly by inhibiting cyclooxygenase and lipoxygenase [48]. To this purpose, it is noteworthy that in rats the infusion of Mg blocks the formation of thrombi after vascular injury by reducing platelet aggregation and prolonging blood clotting time. Accordingly, the intravenous administration of Mg inhibits acute platelet-dependent stent thrombosis both in experimental models and in humans [49, 50].

Endothelial cells are also known to control fibrinolysis. High extracellular Mg reduces the amounts of plasminogen activator inhibitor-1 (PAI-1) [27]. PAI-1 binds to fibrin and protects the clot from tissue plasminogen activator-induced fibrinolysis. It is possible to conclude that the decrease of PAI-1 secretion and storage in the fibrin matrix facilitates the lysis of the clot.

Figure 1 summarizes the effects of high Mg on endothelial cells.

Increase of extracellular Mg concentration promotes events which facilitate endothelialization, prevent thrombosis, reduce inflammation and vascular tone.
Figure 1:

Increase of extracellular Mg concentration promotes events which facilitate endothelialization, prevent thrombosis, reduce inflammation and vascular tone.

Magnesium and smooth muscle cells

Smooth muscle cells predominate in the vascular tunica media where they are primarily implicated in the regulation of the caliber of the vessels through contraction-relaxation in response to vasoconstrictors and vasodilators, thus controlling blood flow distribution in the tissues. In addition, they can perform important functions such as migration, proliferation, synthesis of cytokines, growth factors and ECM components. Actually, vascular smooth muscle cells are fascinating cells with a remarkable plasticity that explains their role in physiology and disease, among which atherosclerosis, hypertension and stenosis.

Several local and systemic factors regulate vascular smooth muscle cell function, and Mg is one of these.

Intracellular Mg homeostasis

Vascular smooth muscle cells express TRPM6 and 7. In particular, TRPM7 plays a role in regulating Mg influx, proliferation, adhesion, migration and contraction and is up-regulated by vasoactive molecules such as angiotensin II and aldosterone [51]. No data are available at the moment about the expression of TRPMs in vascular smooth muscle cells exposed to different concentrations of Mg. It is known that high extracellular Mg causes a 2.5-fold increase of intracellular Mg concentration [21].

High Mg, proliferation, migration and synthesis of ECM proteins

While very high (>20 mM) concentrations of extracellular Mg markedly reduce cell viability, 10 and 15 mM of this metal do not significantly impact on smooth muscle cell proliferation. These results are consistent with FACS analysis revealing that, apart from a modest increase in apoptosis, no changes of cell cycle distribution occur in cells exposed to physiologic or high Mg [21]. Gene expression analysis demonstrates the down-regulation of growth factors, their receptor and metalloproteases upon culture in high Mg. Since these proteins are involved in driving motility, these results suggest that Mg might impair smooth muscle cell migration [21]. In addition, the down-regulation of fibronectin and collagens was reported in cells cultured in high Mg. All the results indicate that high Mg interferes with major events contributing to neointima formation.

Some recent studies focused on the protective role of Mg against vascular calcification, a common complication of atherosclerotic plaques [52]. Indeed, vascular smooth muscle cells can differentiate into osteoblast-like cells and generate matrix for calcium-phosphate deposition in the vascular wall. Increasing Mg levels reduce vascular smooth muscle cell calcification by down-regulating the osteogenic transcription factors Cbfa-1 and osterix, and up-regulating the natural calcification inhibitors matrix Gla protein and osteoprotegerin [53]. TRPM7 is involved in the process since its silencing abrogates the effect [53].

It should be recalled that in smooth muscle cells some effects of extracellular Mg are mediated by its capability to regulate intracellular calcium in large part through its inhibitory effects on various calcium channels. Moreover, Mg modulates the mobilization of calcium from intracellular stores [54]. Calcium is fundamental in controlling cell contraction. Magnesium promotes vasorelaxation in part by antagonizing calcium in part by attenuating the properties of vasoconstrictors and potentiating the actions of vasodilators [39].

Figure 2 summarizes the effects of high Mg on vascular smooth muscle cells.

Increase of extracellular Mg concentration decreases vascular tone, reduces neointima formation and media calcification.
Figure 2:

Increase of extracellular Mg concentration decreases vascular tone, reduces neointima formation and media calcification.

Conclusions

There are strong biological bases supporting the use of biodegradable Mg stents because high local concentrations of Mg might prevent common complications of stent implantation. Indeed, by acting on smooth muscle cells, Mg prevents many of those events that lead to neointima formation, and by acting on endothelial cells Mg contrasts clot formation and reduces inflammatory response. It would be relevant to know the effect of high Mg on the recruitment of endothelial progenitors, which possess a marked regenerative capacity and accelerate re-endothelialization [55]. All these findings might provide challenging issues to generate stents with appropriate mechanical properties and controlled Mg release to optimize vascular healing.

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About the article

Corresponding author: Jeanette A.M. Maier, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via G.B. Grassi 74, Milano I-20157, Italy, Phone: 39-02-50319648, Fax: 39-02-50319659, E-mail:


Received: 2015-01-30

Accepted: 2015-05-07

Published Online: 2015-06-05

Published in Print: 2015-03-01


Citation Information: BioNanoMaterials, Volume 16, Issue 1, Pages 23–29, ISSN (Online) 2193-066X, ISSN (Print) 2193-0651, DOI: https://doi.org/10.1515/bnm-2015-0003.

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