An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission.

Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression.

Development and Implementation of an Integrated Preclinical Atherosclerosis Database.

Background: Basic scientists have used preclinical animal models to explore mechanisms driving human diseases for decades, resulting in thousands of publications, each supporting causative inferences. Despite substantial advances in the mechanistic construct of disease, there has been limited translation from individual studies to advances in clinical care. An integrated approach to these individual studies has the potential to improve translational success.

Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice-Brief Report.

Background: Women with a history of preeclampsia have evidence of premature atherosclerosis and increased risk of myocardial infarction and stroke compared with women who had a normotensive pregnancy. Whether this is due to common risk factors or a direct impact of prior preeclampsia exposure has never been tested in a mouse atherosclerosis model.

Methods: Pregnant LDLR-KO (low-density lipoprotein receptor knockout; n=35) female mice were randomized in midgestation to sFlt1 (soluble fms-like tyrosine kinase 1)-expressing adenovirus or identical control adenovirus.

Development and implementation of an integrated preclinical atherosclerosis database.

Background: Basic scientists have used preclinical animal models to explore mechanisms driving human diseases for decades, resulting in thousands of publications, each supporting causative inferences. Despite substantial advances in the mechanistic construct of disease, there has been limited translation from individual studies to advances in clinical care. An integrated approach to these individual studies has the potential to improve translational success.

Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia.

Background: Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress.

Systems Approach to Integrating Preclinical Apolipoprotein E-Knockout Investigations Reveals Novel Etiologic Pathways and Master Atherosclerosis Network in Humans.

Objective: Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach to integration of preclinical data identifies novel pathways and regulators in human disease. Approach and Results: Of 716 articles published in from 1995 to 2019 using the apolipoprotein E knockout mouse to study atherosclerosis, data were extracted from 360 unique studies in which a gene was experimentally perturbed to impact plaque size or composition and analyzed using Ingenuity Pathway Analysis software.

Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis.

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex.

Mineralocorticoid and Estrogen Receptors in Endothelial Cells Coordinately Regulate Microvascular Function in Obese Female Mice.

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The endothelial mineralocorticoid receptor: Contributions to sex differences in cardiovascular disease.

Cardiovascular disease remains the leading cause of death for both men and women. The observation that premenopausal women are protected from cardiovascular disease relative to age-matched men, and that this protection is lost with menopause, has led to extensive study of the role of sex steroid hormones in the pathogenesis of cardiovascular disease. However, the molecular basis for sex differences in cardiovascular disease is still not fully understood, limiting the ability to tailor therapies to male and female patients.

Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1.

Hippocampal dendritic spine density rapidly increases following estradiol (E ) treatment, but the types of spines and trafficking of synaptic markers have received little investigation. We assessed rapid effects of E over time on the density of four spine types (stubby, filopodial, long thin, and mushroom) and trafficking of AMPA receptor subunit GluA2 and PSD95 on tertiary, apical dendrites in CA1. Castrated male rats received 20 μg kg of E or vehicle and were sacrificed 30 or 120 min later.