Gradual not sudden change: multiple sites of functional transition across the microvascular bed

In understanding the role of the neurovascular unit as both a biomarker and target for disease interventions, it is vital to appreciate how the function of different components of this unit change along the vascular tree. The cells of the neurovascular unit together perform an array of vital functions, protecting the brain from circulating toxins and infection, while providing nutrients and clearing away waste products. To do so, the brain’s microvasculature dilates to direct energy substrates to active neurons, regulates access to circulating immune cells, and promotes angiogenesis in response to decreased blood supply, as well as pulsating to help clear waste products and maintain the oxygen supply. Different parts of the cerebrovascular tree contribute differently to various aspects of these functions, and previously, it has been assumed that there are discrete types of vessel along the vascular network that mediate different functions. Another option, however, is that the multiple transitions in function that occur across the vascular network do so at many locations, such that vascular function changes gradually, rather than in sharp steps between clearly distinct vessel types. Here, by reference to new data as well as by reviewing historical and recent literature, we argue that this latter scenario is likely the case and that vascular function gradually changes across the network without clear transition points between arteriole, precapillary arteriole and capillary. This is because classically localized functions are in fact performed by wide swathes of the vasculature, and different functional markers start and stop being expressed at different points along the vascular tree. Furthermore, vascular branch points show alterations in their mural cell morphology that suggest functional specializations irrespective of their position within the network. Together this work emphasizes the need for studies to consider where transitions of different functions occur, and the importance of defining these locations, in order to better understand the vascular network and how to target it to treat disease

Supporting Data for Gradual Not Sudden Change: Multiple Sites of Functional Transition Across the Microvascular Bed

The data provided was used to generate the figures in Shaw et al (2022); Gradual Not Sudden Change: Multiple Sites of Functional Transition Across the Microvascular Bed, Frontiers in Aging Neuroscience. Full details of how the data was generated and processed is provided in that paper. The ReadMe file attached to this record gives details on the data including measurements and column headings.A single Excel spreadsheet containing all the data points used for graphs in Figures 4-9 and Supplementary Figures 3-6 as individual work sheets (uploaded as .xlsx), and individual .csv files containing all the data points used for graphs in Figures 4-9 and Supplementary Figures 2-6 (for non-proprietary format). Abstract In understanding the role of the neurovascular unit as both a biomarker and target for disease interventions, it is vital to appreciate how the function of different components of this unit change along the vascular tree. The cells of the neurovascular unit together perform an array of vital functions, protecting the brain from circulating toxins and infection, while providing nutrients and clearing away waste products. To do so, the brain’s microvasculature dilates to direct energy substrates to active neurons, regulates access to circulating immune cells, and promotes angiogenesis in response to decreased blood supply, as well as pulsating to help clear waste products and maintain the oxygen supply. Different parts of the cerebrovascular tree contribute differently to various aspects of these functions, and previously, it has been assumed that there are discrete types of vessel along the vascular network that mediate different functions. Another option, however, is that the multiple transitions in function that occur across the vascular network do so at many locations, such that vascular function changes gradually, rather than in sharp steps between clearly distinct vessel types. Here, by reference to new data as well as by reviewing historical and recent literature, we argue that this latter scenario is likely the case and that vascular function gradually changes across the network without clear transition points between arteriole, precapillary arteriole and capillary. This is because classically localised functions are in fact performed by wide swathes of the vasculature, and different functional markers start and stop being expressed at different points along the vascular tree. Furthermore, vascular branch points show alterations in their mural cell morphology that suggest functional specialisations irrespective of their position within the network. Together this work emphasises the need for studies to consider where transitions of different functions occur, and the importance of defining these locations, in order to better understand the vascular network and how to target it to treat disease. <br

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo