Initiation and Propagation of Vascular Calcification Is Regulated by a Concert of Platelet- and Smooth Muscle Cell-Derived Extracellular Vesicles

Abstract

The ageing population continues to suffer from its primary killer, cardiovascular disease (CVD). Despite recent advances in interventional medicinal and surgical therapies towards the end of the 20th century, the epidemic of cardiovascular disease has not been halted. Yet, rather than receding globally, the burden of CVD has risen to become a top cause of morbidity and mortality worldwide. Most CVD arises from thrombotic rupture of an atherosclerotic plaque, the pathologic thickening of coronary and carotid artery segments and subsequent distal ischemia in heart or brain. In fact, one-fifth of deaths are directly attributable to thrombotic rupture of a vulnerable plaque. Atherosclerotic lesion formation is caused by a concert of interactions between circulating leukocytes and platelets, interacting with the endothelial barrier, signalling into the arterial wall by the release of cytokines and extracellular vesicles (EVs). Both platelet- and cell-derived EVs represent a novel mechanism of cellular communication, particularly by the transport and transfer of cargo and by reprogramming of the recipient cell. These interactions result in phenotypic switching of vascular smooth muscle cells (VSMCs) causing migration and proliferation, and subsequent secretion of EVs. Loss of VSMCs attracts perivascular Mesenchymal Stem Cells (MSCs) from the adventitia, which are a source of VSMCs and contribute to repair after vascular injury. However, continuous stress stimuli eventually switch phenotype of cells into osteochondrogenic VSMCs facilitating vascular calcification. Although Virchow’s triad is over 100 years old, it is a reality that is accurate today. It can be briefly summarised as changes in the composition of blood (platelet EVs), alterations in the vessel wall (VSMC phenotypic switching, MSC infiltration and EV release) and disruption of blood flow (atherothrombosis). In this paper, we review the latest relevant advances in the identification of extracellular vesicle pathways as well as VSMCs and pericyte/MSC phenotypic switching, underlying vascular calcification.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…VSMCs are the most abundant cell type in vasculature and are critical for maintaining homeostasis due to their functions in the vascular system. VSMCs are characterized by their capacity to contract and relax, as well as in vessel remodeling [141]. Furthermore, Lacolley et al recently provided a new perspective for understanding the role of VSMCs in arterial stiffness and how interactions with ECs can regulate vascular aging [120].…”

“…Moreover, some VSMCs do not achieve senescence and suffer proliferation. The increase in proliferative VSMCs is associated with an increased release of the extracellular matrix (ECM) to the wall, thereby augmenting vascular wall thickness and stiffness [141].…”

“…Aging per se and age-associated pathologies generate senescent VSMCs that undergo phenotype changes. These changes include quiescent contractile phenotypes (differentiated VSMCs) and synthetic phenotypes (dedifferentiated VSMCs) characterized by reduced expression of SMC-specific contractile proteins (α-SMA, SM-MHC, and calponin), as well as increased cell proliferation and production of pro-inflammatory cytokines in differentiated VSMCs [120,141]. At present, cells are understood to reduce their contractile capacity, migration, proliferation, and reduce ECM production.…”

“…When a vessel is damaged, a piece of machinery for repair is triggered, and the migration mechanism and proliferation of VSMCs are critical. Accordingly, this entails an increase in the abundance of growth factors (PDGF, TGF, and VEGF) and the volume of the ECM, with the ultimate purpose of reconstructing the vasculature following injury [120,[141][142][143].…”

Indoxil sulfato induce senescencia y liberación de microvesículas en células endoteliales que promueven la calcificación vascular

“…La calcificación en las células vasculares va a producirse por una cadena de señales que terminan en una transformación osteogénica y que comienza con las MV liberadas por las células [15] al actuar como una señal en el proceso de calcificación donde se regula el equilibrio entre el fósforo inorgánico y el calcio [3]. Además, las células musculares lisas vasculares (CMLV) se vuelven susceptibles a la acción de las MV y sufren una desdiferenciación progresiva en su fenotipo, haciendo que se asemejen a los osteoblastos [16].…”