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Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention.

Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinson’s disease (PD). We prospectively evaluated a Parkinson’s cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [123I][β]-CIT and single-photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor-related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [123I][β]-CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long-term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation.

Events responsible for cardiovascular mortality and morbidity are predominantly caused by rupture of "vulnerable" atherosclerotic lesions. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and have historically been considered beneficial for plaque stability. VSMCs constitute the main cellular component of the protective fibrous cap within lesions and are responsible for synthesising strengthgiving extracellular matrix components. However, lineage-tracing experiments in mouse models of atherosclerosis have shown that, in addition to the fibrous cap, VSMCs also give rise to many of the cell types found within the plaque core. In particular, VSMCs generate a substantial fraction of lipid-laden foam cells, and VSMC-derived cells expressing markers of macrophages, osteochondrocyte, and mesenchymal stem cells have been observed within lesions. Here, we review recent studies that have changed our perspective on VSMC function in atherosclerosis and discuss how VSMCs could be targeted to increase plaque stability.

Extracellular matrix (ECM) remodeling occurs during normal homeostasis and also plays an important role during development, tissue repair, and in various disease processes. ECM remodeling involves changes in the synthesis, deposition, and degradation of ECM molecules. ECM molecules can be degraded extracellularly, as well as intracellularly following endocytosis. Our data show that the ECM protein fibronectin is an important regulator of ECM remodeling. We previously showed that agents that inhibit the polymerization of fibronectin into ECM fibrils promote the loss of preexisting fibronectin matrix and accelerate fibronectin endocytosis and degradation. In this paper we show that inhibition of fibronectin polymerization leads to the loss of collagen I matrix fibrils and a corresponding increase in the levels of endocytosed collagen I. In contrast, manipulations that stabilize fibronectin matrix fibrils, such as caveolin-1 depletion, stabilize collagen I matrix fibrils and cause a decrease in ECM collagen I endocytosis. Our data also show that endocytosis of ECM collagen I is regulated by both ␤1 integrins and Endo180/urokinase plasminogen activator associated protein (uPARAP). Unexpectedly, Endo180/uPARAP was also shown to promote the endocytosis of fibronectin from the ECM. These data demonstrate that fibronectin polymerization regulates the remodeling of ECM collagen I, in part, by regulating collagen I endocytosis. Furthermore, these data show that processes that regulate ECM deposition coordinately regulate the removal of proteins from the ECM. These data highlight the complexity of ECM remodeling. This multifaceted regulatory process may be important to ensure tight regulation of ECM fibronectin and collagen I levels. extracellular matrix; integrin; endocytosis; Endo180; urokinase plasminogen activator-associated protein EXTRACELLULAR MATRIX (ECM) remodeling is a critical process that occurs during development and tissue repair. ECM remodeling also occurs in a variety of pathological conditions, such as hypertension, restenosis following angioplasty, heart failure, fibrosis, and cancer (1,4,39,68). ECM synthesis, deposition, and degradation are all components of ECM remodeling. The balance between these processes determines whether net accumulation or loss of ECM occurs. Different ECM proteins, and combinations of proteins, can have distinct effects on the phenotype of cells, affecting such important processes as cell survival, growth, differentiation, and migration (2,42,55,59,64). Additionally, ECM fragments produced by proteolysis can accumulate in vivo and contribute to changes in cell behavior (3,24,44,63). ECM fragments can have properties distinct from the intact parental proteins (8,14,41). Hence, mechanisms that limit the accumulation of ECM fragments are likely to be important for regulating a variety of cell processes.A variety of extracellular proteases regulate ECM degradation. Prominent among these proteases are matrix metalloproteinases (MMPs). MMPs are important regulators of cell migration ...