Sox9 Accelerates Vascular Aging by Regulating Extracellular Matrix Composition and Stiffness.

BACKGROUND: Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular aging. Sox9 (SRY-box transcription factor 9) has been implicated in vascular smooth muscle cell (VSMC) osteo/chondrogenic conversion; however, its relationship with aging and calcification has not been studied. METHODS: Immunohistochemistry was performed on human aortic samples from young and aged patients. Young and senescent primary human VSMCs were induced to produce ECM, and Sox9 expression was manipulated using adenoviral overexpression and depletion. ECM properties were characterized using atomic force microscopy and proteomics, and VSMC phenotype on hydrogels and the ECM were examined using confocal microscopy. RESULTS: In vivo, Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16 (cyclin-dependent kinase inhibitor 2A). In vitro Sox9 showed mechanosensitive responses with increased expression and nuclear translocation in senescent cells and on stiff matrices. Sox9 was found to regulate ECM stiffness and organization by orchestrating changes in collagen (Col) expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs, whereby senescent cells plated on ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. LH3 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3) was identified as an Sox9 target and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles and Sox9 promotes extracellular vesicle secretion, leading to increased LH3 deposition within the ECM. CONCLUSIONS: These findings highlight the crucial role of ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle, whereby cellular senescence and increased ECM stiffening promote Sox9 expression, which, in turn, drives further ECM modifications to further accelerate stiffening and senescence.

Examining predictors of initial outpatient psychiatric treatment for conduct problems in youth: A records review.

PURPOSE: To investigate predictors of conduct problem (CP) treatment in an outpatient child psychiatry clinic. DESIGN AND METHODS: Medical records (N = 78) of youth with CPs (71% male; mean age = 9.9 years) were analyzed to determine how treatment history, race, gender, travel distance, aggression symptoms, internalizing disorder symptoms, and age of diagnosis influenced initial treatment decisions. FINDINGS: Severity of aggression symptoms and travel distance significantly increased the likelihood that initial treatments included psychotropic medication. Travel distance also moderated the relationship between history of psychosocial intervention for CPs and treatment recommendations. PRACTICE IMPLICATIONS: Adhering to treatment guidelines for youth with CPs is essential for furthering evidence-based psychiatric nursing care.

Current state of evidence for medication treatment of preschool internalizing disorders.

Psychotropic medications are being prescribed off-label by psychiatrists to treat preschool children diagnosed with internalizing disorders. In this review, the current state of evidence is presented for medications used to treat preschool children (ages 2-5 year olds) diagnosed with anxiety and/or depressive disorders. Eleven studies were systematically identified for this review based on a priori criteria. Overall, the available literature revealed that studies addressing the medication treatment of internalizing disorders in preschoolers are extremely limited and represent relatively weak research methodologies. Given the increasing prevalence of the use of psychotropic medications to treat preschool children and the unique challenges associated with working with this population, it is imperative that mental health practitioners are aware of the current, albeit limited, research on this practice to help make informed treatment decisions. Suggestions about how to monitor potential costs and benefits in those unique cases in which psychopharmacological treatments might be considered for young children are given. Moreover, areas of additional research for this population are discussed.