Vascular calcifications (VCs) are actively regulated biological processes associated with crystallization of hydroxyapatite in the extracellular matrix and in cells of the media (VCm) or intima (VCi) of the arterial wall. Both patterns of VC often coincide and occur in patients with type II diabetes, chronic kidney disease, and other less frequent disorders; VCs are also typical in senile degeneration. In this article, we review the current state of knowledge about the pathology, molecular biology, and nosology of VCm, expand on potential mechanisms responsible for poor prognosis, and expose some of the directions for future research in this area.

Medial arterial calcification (MAC) characterizes human arterial ageing, potentially remaining clinically silent for decades. However, in susceptible individuals and patients with diabetes mellitus and chronic kidney disease, it becomes a critical risk factor for cardiovascular morbidity and mortality, and it is a significant risk factor for chronic limb-threatening ischaemia and limb amputation. A key biological feature of MAC pathogenesis is the phenotype switching of vascular smooth muscle cells, ultimately responsible for the deposition of hydroxyapatite crystals and the progressive medial layer destruction associated with intimal thickening. The signalling pathways targeting the vascular smooth muscle cells in ageing and disease are partly shared. Due to the MAC-related arterial wall stiffening and intimal thickening, MAC fundamentally alters central and peripheral haemodynamics. Yet, a comprehensive understanding of MAC’s impact on haemodynamics is lacking. Ankle-brachial index, ultrasound, and X-ray radiography can detect only advanced MAC in the clinical setting. Due to the slow progression, MAC provides many early detection, prevention, and timely intervention targets. However, no effective pharmacological treatment is currently available to alter its course, and revascularizations remain the only treatment option in symptomatic patients. To prevent, reverse, or delay MAC, further research is needed to reveal the complete picture of molecular pathogenesis and haemodynamic impact of MAC vasculopathy.

Media sclerosis (MS) and peripheral artery disease (PAD) may coincide, particularly in type 2 diabetics (T2D) and in patients with chronic kidney disease (CKD). In contrast to non-diabetics, in T2D PAD is more severe and more distal. Although MS is suspected to play a role, the underlying pathophysiological reasons for the differences still remain elusive today. We tested the hypothesis that MS is a promoter of atherosclerosis as it occurs in T2D with PAD by interfering with arterial remodeling using an in-silico simulation. We confirmed that MS aggravates PAD by promoting negative remodeling. We found that the effect is more pronounced in smaller distal arteries compared to larger proximal ones. Our results suggest that the degree of this divergence depends on the ratio between the thickness of the intima relative to the thickness of the media/adventitia of the individually affected arteries.

Medial vascular calcification (MVC) is a degenerative process that involves the deposition of calcium in the arteries, with a high prevalence in chronic kidney disease (CKD), diabetes, and aging. Calcification is the process of precipitation largely of calcium phosphate, governed by the laws of thermodynamics that should be acknowledged in studies of this disease. Amorphous calcium phosphate (ACP) is the key constituent of early calcifications, mainly composed of Ca²⁺and PO₄^3–ions, which over time transform into hydroxyapatite (HAP) crystals. The supersaturation of ACP related to Ca²⁺and PO₄^3–activities establishes the risk of MVC, which can be modulated by the presence of promoter and inhibitor biomolecules. According to the thermodynamic parameters, the process of MVC implies: (i) an increase in Ca²⁺and PO₄^3–activities (rather than concentrations) exceeding the solubility product at the precipitating sites in the media; (ii) focally impaired equilibrium between promoter and inhibitor biomolecules; and (iii) the progression of HAP crystallization associated with nominal irreversibility of the process, even when the levels of Ca²⁺and PO₄^3–ions return to normal. Thus, physical-chemical processes in the media are fundamental to understanding MVC and represent the most critical factor for treatments’ considerations. Any pathogenetical proposal must therefore comply with the laws of thermodynamics and their expression within the medial layer.