Targeting Matrix Vesicles in Vascular Calcification
Calcification of tissues is a feature of aging, and problematic in blood vessels and heart tissue. It reduces elasticity and cardiovascular tissue function, leading to eventually fatal problems. The underlying mechanisms that drive calcification likely involve the inflammatory signaling produced by senescent cells, contributing to the shift in behavior that makes cells in blood vessel walls act more like osteoblasts, attempting to build bone by depositing calcium structures in the tissue. As noted here, the roots of calcification remain much debated, and there is plenty of room for new discoveries.
Vascular calcification (VC) is a prominent clinical pathology of atherosclerosis, diabetes mellitus, hypertension, aging, and chronic kidney disease (CKD), resulting in abnormal calcium phosphate accumulation in the intimal and medial layers of the vessel wall. After vascular calcification, the stiffness of the vascular wall is increased, and the compliance is decreased, which results in myocardial ischemia, left ventricular hypertrophy, and heart failure. At present, vascular calcification is still lacks effective treatment methods, and the pathogenesis mechanism remains unclear.
The phenotype switching of vascular smooth muscle cells (VSMCs) has been regarded as the principal driver in the calcification of intimal and medial layers. VSMCs undergo the phenotypic transformation from a differentiated "contractile" into a dedifferentiated "synthetic" proliferative phenotype in the process of vascular calcification. The phenotypic switching VSMCs express higher osteoblast-like markers, and is associated with increased proliferation and migration ability. The osteoblast-like phenotype of VSMCs is regarded as the cellular characteristic factor of vascular calcification. Many factors such as oxidative stress damage, hyperphosphatemic environment, and inflammation increase the indices related to bone formation in VSMCs and promote their transformation into osteoblasts. On the other hand, a variety of biochemical factors are also involved in the phenotype switching of VSMCs.
Matrix vesicles (MVs), one kind of extracellular matrix derived extracellular vesicles (EVs), are membrane-bound microparticles released by cells, containing various cargo, including proteins, carbohydrates, lipids, DNA and small RNAs, such as microRNAs (miRNAs). The origin and composition of MVs determine their calcification potential. Recent evidence showed that extracellular MVs serve as nucleating foci to initiate microcalcification. The formation and secretion of MVs and the increase of intracellular alkaline phosphatase (ALP) activity are also involved in the osteoblast-like phenotype transformation of VSMCs.
However, the specific mechanisms and functions of MVs regulating vascular calcification have not been fully elucidated. For example, what is the originating cell that releases MVs in vascular calcification, and how do the pro-calcification MVs get into the recipient cell? This article aims to review the detailed role of MVs in the progression of VC and compare the difference with other major drivers of calcification, including aging, uremia, mechanical stress, oxidative stress, and inflammation. We will also bring attention to the novel findings in the isolation and characterization of MVs, and the therapeutic application of MVs in VC.