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Cardiovascular disease (CVD) is largely preventable, and the leading cause of death for men and women. Though women have increased life expectancy compared to men, there are marked sex disparities in prevalence and risk of CVD-associated mortality and dementia. Yet, the basis for these and female-male differences is not completely understood. It is increasingly recognized that heart and brain health represent a lifetime of exposures to shared risk factors (including obesity, hyperlipidemia, diabetes, and hypertension) that compromise cerebrovascular health. We describe the process and resources for establishing a new research Center for Women’s Cardiovascular and Brain Health at the University of California, Davis as a model for: (1) use of the cy pres principle for funding science to improve health; (2) transdisciplinary collaboration to leapfrog progress in a convergence science approach that acknowledges and addresses social determinants of health; and (3) training the next generation of diverse researchers. This may serve as a blueprint for future Centers in academic health institutions, as the cy pres mechanism for funding research is a unique mechanism to leverage residual legal settlement funds to catalyze the pace of scientific discovery, maximize innovation, and promote health equity in addressing society’s most vexing health problems.

Background The mechanisms linking menopausal age and heart failure (HF) incidence are controversial. We investigated for heterogeneity by obesity on the relationship between menopausal age and HF incidence. Methods and Results Using postmenopausal women who attended the Atherosclerosis Risk in Communities Study Visit 4, we estimated hazard ratios of incident HF associated with menopausal age using Cox proportional hazards models, testing for effect modification by obesity and adjusting for HF risk factors. Women were categorized by menopausal age:

Cerebral blood vessels are lined with endothelial cells and form the blood-brain barrier. Their dysfunction constitutes a crucial event in the physiopathology of neurodegenerative disorders and cognitive impairment. Epicatechin can improve cognitive functions and lower the risk for Alzheimer’s disease or stroke. However, molecular mechanisms of epicatechin on brain vascular endothelium are still unexplored. The objective of this study was to investigate the biological effects of gut microbiome-derived metabolites of epicatechin, 5-(4′-Hydroxyphenyl)-γ-valerolactone-3′-sulfate and 5-(4′-Hydroxyphenyl)-γ-valerolactone-3′-O-glucuronide, in TNF-α-stimulated human brain microvascular endothelial cells at low (nM) concentrations by evaluating their multi-omic modification (expression of mRNA, microRNA, long non-coding RNAs, and proteins). We observed that metabolites are biologically active and can simultaneously modulate the expression of protein-coding and non-coding genes as well as proteins. Integrative bioinformatics analysis of obtained data revealed complex networks of genomics modifications by acting at different levels of regulation. Metabolites modulate cellular pathways including cell adhesion, cytoskeleton organization, focal adhesion, signaling pathways, pathways regulating endothelial permeability, and interaction with immune cells. This study demonstrates multimodal mechanisms of action by which epicatechin metabolites could preserve brain vascular endothelial cell integrity, presenting mechanisms of action underlying epicatechin neuroprotective properties.

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia. [ABSTRACT FROM AUTHOR]

Biological sex and a high glycemic diet (HGD) contribute to dementia, yet little is known about the operative molecular mechanisms. Our goal was to understand the differences between males and females in the multi-genomic response of the hippocampal microvasculature to the HGD, and whether there was vasculoprotection via the inhibition of soluble epoxide hydrolase (sEHI). Adult wild type mice fed high or low glycemic diets for 12 weeks, with or without an sEHI inhibitor (t-AUCB), had hippocampal microvessels isolated by laser-capture microdissection. Differential gene expression was determined by microarray and integrated multi-omic bioinformatic analyses. The HGD induced opposite effects in males and females: the HGD-upregulated genes were involved in neurodegeneration or neuroinflammation in males, whereas in females they downregulated the same pathways, favoring neuroprotection. In males, the HGD was associated with a greater number of clinical diseases than in females, the sEHI downregulated genes involved in neurodegenerative diseases to a greater extent with the HGD and compared to females. In females, the sEHI downregulated genes involved in endothelial cell functions to a greater extent with the LGD and compared to males. Our work has potentially important implications for sex-specific therapeutic targets for vascular dementia and cardiovascular diseases in males and females. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia. [ABSTRACT FROM AUTHOR]

Background: In response to the landmark report "Beyond Bias and Barriers: Fulfilling the Potential of Women in Academic Science and Engineering," the NIH Office of Research on Women's Health issued a request for applications that funded 14 R01 grants to investigate causal factors to career success for women in STEM. Following completion of the 4-year grants, the grant PIs formed a grassroots collaborative, the Research Partnership on Women in Science Careers.Objective: To summarize the work of the Research Partnership, which resulted in over 100 publications.Methods: We developed six themes to organize the publications, with a "Best Practices" for each theme at the end of each section: Barriers to Career Advancement; Mentoring, Coaching, and Sponsorship; Career Flexibility and Work-Life Balance; Pathways to Leadership; Compensation Equity; and Advocating for Change and Stakeholder Engagement.Results: Women still contend with sexual harassment, stereotype threat, a disproportionate burden of family responsibilities, a lack of parity in compensation and resource allocation, and implicit bias. Strategies to address these barriers using the Bronfenbrenner ecological model at the individual, interpersonal, institutional, academic community, and policy levels include effective mentoring and coaching, having a strong publication record, addressing prescriptive gender norms, positive counter-stereotype imaging, career development training, networking, and external career programs such as the AAMC Early and Mid-Career Programs and Executive Leadership in Academic Medicine (ELAM).Conclusions: Cultural transformation is needed to address the barriers to career advancement for women. Implementing the best practices noted of the work of the Research Partnership can help to achieve this goal. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the number one cause of death in women. It is estimated that 44 million women in the United States are either living with or at risk for heart disease. This article highlights the recent significant progress made in improving care, clinical decision-making, and policy implications for women with CVD. We provide our perspective supported by evidence-based advances in cardiovascular research and clinical care guidelines in seven areas: (1) primary CVD prevention and community heart care, (2) secondary prevention of CVD, (3) stroke, (4) heart failure and cardiomyopathies, (5) ischemia with nonobstructive coronary artery disease, (6) spontaneous coronary artery dissection, and (7) arrhythmias and device therapies. Advances in these fields have improved the lives of women living with and at risk for heart disease. With increase awareness, partnership with national organizations, sex-specific research, and changes in policy, the morbidity and mortality of CVD in women can be further reduced. [ABSTRACT FROM AUTHOR]

Membership in medical societies is associated with a number of benefits to members that may include professional education, opportunities to present research, scientific and/or leadership training, networking, and others. In this perspective article, the authors address the value that medical specialty society membership and inclusion have in the development of an academic physician's career and how underrepresentation of women may pose barriers to their career advancement. Because society membership itself is not likely sufficient to support the advancement of academic physicians, this report focuses on one key component of advancement that also can be used as a measure of inclusion in society activities-the representation of women physicians among recipients of recognition awards. Previous reports demonstrated underrepresentation of women physicians among recognition award recipients from 2 physical medicine and rehabilitation specialty organizations, including examples of zero or near-zero results. This report investigated whether zero or near-zero representation of women physicians among recognition award recipients from medical specialty societies extended beyond the field of physical medicine and rehabilitation. Examples of the underrepresentation of women physicians, as compared with their presence in the respective field, was found across a range of additional specialties, including dermatology, neurology, anesthesiology, orthopedic surgery, head and neck surgery, and plastic surgery. The authors propose a call for action across the entire spectrum of medical specialty societies to: (1) examine gender diversity and inclusion data through the lens of the organization's mission, values, and culture; (2) transparently report the results to members and other stakeholders including medical schools and academic medical centers; (3) investigate potential causes of less than proportionate representation of women; (4) implement strategies designed to improve inclusion; (5) track outcomes as a means to measure progress and inform future strategies; and (6) publish the results to engage community members in conversation about the equitable representation of women. [ABSTRACT FROM AUTHOR]

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While regulation of receptor function is known to occur at many levels (e.g. transcriptional, post-translational), it is generally perceived that a tissue either expresses or does not express a particular receptor in an all-ornone fashion. Many pathological (e.g. tissue injury) and physiological (e.g. angiogenesis) processes have, however, been shown to be associated with the transcriptional induction of specific receptors. Induced receptors are not confined to any particular class, but range from G protein-coupled receptors to receptor tyrosine kinases. The potential implications of de novo receptor expression are profound with respect to potential novel therapeutic targets in specific disease states. Further, this observation may explain unexpected side-effects in the pharmacotherapy of existing disease states. In this article Lucy Donaldson, Michael Hanley and Amparo Villablanca discuss circumstances under which de novo receptor induction has been described, potential mechanisms of induction and the implications for pharmacology.

Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain's microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer's dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH. [ABSTRACT FROM AUTHOR]