ABSTRACT
The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, are able to invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis and here we show that FN stimulates VSMCs to secrete small extracellular vesicles (sEVs) by activating the ß1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. Spatially, sEV were secreted via filopodia-like cellular protrusions at the leading edge of migrating cells. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI. In vitro assays identified collagen VI as playing the key role in cell adhesion and invasion. Taken together our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collage VI enriched sEVs by VSMCs. These sEVs stimulate migration and invasion by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction forces to enable VSMC movement within the complex vascular ECM network.
ABSTRACT
PURPOSE OF REVIEW: This review examines the current knowledge and recent developments in the field of vascular calcification focusing on the emerging role of senescence and inflammation in driving this disorder and exploring the overlap and relevance of these pathways to calcinosis in rheumatic disease. RECENT FINDINGS: Vascular calcification is an age-associated disorder. Recent studies have identified DNA damage, cellular senescence and consequent inflammation as key drivers of vascular smooth muscle cell osteogenic change and mineralization. Similar ageing and inflammatory factors are associated with calcinosis in rheumatic disease and some are targets of experimental drugs currently undergoing clinical trials. SUMMARY: Calcinosis in the vascular system and in rheumatic disease share similarities in terms of biomineralization and cardiovascular outcomes. Although research into the role of senescence and inflammation has recently been advanced in vascular calcification, little is known about the mechanistic role of inflammation in calcinosis in rheumatic disease. This review explores whether lessons from one calcinosis can be transferred and applied to the other to provide further insights and inform treatment strategies.
