Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells.

The evolution of the circulatory system from invertebrates to mammals has involved the passage from an open system to a closed in-parallel system via a closed in-series system, accompanying the increasing complexity and efficiency of life's biological functions. The archaic heart enables pulsatile motion waves of hemolymph in invertebrates, and the in-series circulation in fish occurs with only an endothelium, whereas mural smooth muscle cells appear later. The present review focuses on evolution of the circulatory system. In particular, we address how and why this evolution took place from a closed, flowing, longitudinal conductance at low pressure to a flowing, highly pressurized and bifurcating arterial compartment. However, although arterial pressure was the latest acquired hemodynamic variable, the general teleonomy of the evolution of species is the differentiation of individual organ function, supported by specific fueling allowing and favoring partial metabolic autonomy. This was achieved via the establishment of an active contractile tone in resistance arteries, which permitted the regulation of blood supply to specific organ activities via its localized function-dependent inhibition (active vasodilation). The global resistance to viscous blood flow is the peripheral increase in frictional forces caused by the tonic change in arterial and arteriolar radius, which backscatter as systemic arterial blood pressure. Consequently, the arterial pressure gradient from circulating blood to the adventitial interstitium generates the unidirectional outward radial advective conductance of plasma solutes across the wall of conductance arteries. This hemodynamic evolution was accompanied by important changes in arterial wall structure, supported by smooth muscle cell functional plasticity, including contractility, matrix synthesis and proliferation, endocytosis and phagocytosis, etc. These adaptive phenotypic shifts are due to epigenetic regulation, mainly related to mechanotransduction. These paradigms actively participate in cardio-arterial pathologies such as atheroma, valve disease, heart failure, aneurysms, hypertension, and physiological aging.

Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice.

Evolutionary adaptation to extreme environments often requires coordinated changes in multiple intersecting physiological pathways, but how such multi-trait adaptation occurs remains unresolved. Transcription factors, which regulate the expression of many genes and can simultaneously alter multiple phenotypes, may be common targets of selection if the benefits of induced changes outweigh the costs of negative pleiotropic effects. We combined complimentary population genetic analyses and physiological experiments in North American deer mice (Peromyscus maniculatus) to examine links between genetic variation in transcription factors that coordinate physiological responses to hypoxia (hypoxia-inducible factors, HIFs) and multiple physiological traits that potentially contribute to high-altitude adaptation. First, we sequenced the exomes of 100 mice sampled from different elevations and discovered that several SNPs in the gene Epas1, which encodes the oxygen sensitive subunit of HIF-2α, exhibited extreme allele frequency differences between highland and lowland populations. Broader geographic sampling confirmed that Epas1 genotype varied predictably with altitude throughout the western US. We then discovered that Epas1 genotype influences heart rate in hypoxia, and the transcriptomic responses to hypoxia (including HIF targets and genes involved in catecholamine signaling) in the heart and adrenal gland. Finally, we used a demographically-informed selection scan to show that Epas1 variants have experienced a history of spatially varying selection, suggesting that differences in cardiovascular function and gene regulation contribute to high-altitude adaptation. Our results suggest a mechanism by which Epas1 may aid long-term survival of high-altitude deer mice and provide general insights into the role that highly pleiotropic transcription factors may play in the process of environmental adaptation.

Cardiovascular development and survival require Mef2c function in the myocardial but not the endothelial lineage.

MEF2C is a member of the highly conserved MEF2 family of transcription factors and is a key regulator of cardiovascular development. In mice, Mef2c is expressed in the developing heart and vasculature, including the endothelium. Loss of Mef2c function in germline knockout mice leads to early embryonic demise and profound developmental abnormalities in the cardiovascular system. Previous attempts to uncover the cause of embryonic lethality by specifically disrupting Mef2c function in the heart or vasculature failed to recapitulate the global Mef2c knockout phenotype and instead resulted in relatively minor defects that did not compromise viability or result in significant cardiovascular defects. However, previous studies examined the requirement of Mef2c in the myocardial and endothelial lineages using Cre lines that begin to be expressed after the expression of Mef2c has already commenced. Here, we tested the requirement of Mef2c in the myocardial and endothelial lineages using conditional knockout approaches in mice with Cre lines that deleted Mef2c prior to onset of its expression in embryonic development. We found that deletion of Mef2c in the early myocardial lineage using Nkx2-5Cre resulted in cardiac and vascular abnormalities that were indistinguishable from the defects in the global Mef2c knockout. In contrast, early deletion of Mef2c in the vascular endothelium using an Etv2::Cre line active prior to the onset of Mef2c expression resulted in viable offspring that were indistinguishable from wild type controls with no overt defects in vascular development, despite nearly complete early deletion of Mef2c in the vascular endothelium. Thus, these studies support the idea that the requirement of MEF2C for vascular development is secondary to its requirement in the heart and suggest that the observed failure in vascular remodeling in Mef2c knockout mice results from defective heart function.

Higher Anxiety Is Associated with Lower Cardiovascular Autonomic Function in Female Twins.

Anxiety symptoms co-occur with cardiovascular health problems, with increasing evidence suggesting the role of autonomic dysfunction. Yet, there is limited behavior genetic research on underlying mechanisms. In this twin study, we investigated the phenotypic, genetic and environmental associations between a latent anxiety factor and three cardiovascular autonomic function factors: interbeat interval (IBI, time between heart beats), heart rate variability (HRV, overall fluctuation of heart-beat intervals) and baroreflex sensitivity (BRS, efficiency in regulating blood pressure [BP]). Multivariate twin models were fit using data of female twins (N = 250) of the Twin Interdisciplinary Neuroticism Study (TWINS). A significant negative association was identified between latent anxiety and BRS factors (r = -.24, 95% CI [-.40, -.07]). Findings suggest that this relationship was mostly explained by correlated shared environmental influences, and there was no evidence for pleiotropic genetic or unique environmental effects. We also identified negative relationships between anxiety symptoms and HRV (r = -.17, 95% CI [-.34, .00]) and IBI factors (r = -.13, 95% CI [-.29, .04]), though these associations did not reach statistical significance. Findings implicate that higher anxiety scores are associated with decreased efficiency in short-term BP regulation, providing support for autonomic dysfunction with anxiety symptomatology. The baroreflex system may be a key mechanism underlying the anxiety-cardiovascular health relationship.

Exosomes: Fundamental Biology and Roles in Cardiovascular Physiology.

Exosomes are nanosized membrane particles that are secreted by cells that transmit information from cell to cell. The information within exosomes prominently includes their protein and RNA payloads. Exosomal microRNAs in particular can potently and fundamentally alter the transcriptome of recipient cells. Here we summarize what is known about exosome biogenesis, content, and transmission, with a focus on cardiovascular physiology and pathophysiology. We also highlight some of the questions currently under active investigation regarding these extracellular membrane vesicles and their potential in diagnostic and therapeutic applications.

Coordination of cardiac rhythmic output and circadian metabolic regulation in the heart.

Over the course of a 24-h day, demand on the heart rises and falls with the sleep/wake cycles of the organism. Cardiac metabolism oscillates appropriately, with the relative contributions of major energy sources changing in a circadian fashion. The cardiac peripheral clock is hypothesized to drive many of these changes, yet the precise mechanisms linking the cardiac clock to metabolism remain a source of intense investigation. Here we summarize the current understanding of circadian alterations in cardiac metabolism and physiology, with an emphasis on novel findings from unbiased transcriptomic studies. Additionally, we describe progress in elucidating the links between the cardiac peripheral clock outputs and cardiac metabolism, as well as their implications for cardiac physiology.

Regulators of G protein signaling in cardiovascular function during pregnancy.

G protein-coupled receptor signaling mechanisms are implicated in many aspects of cardiovascular control, and dysfunction of such signaling mechanisms is commonly associated with disease states. Investigators have identified a large number of regulator of G protein signaling (RGS) proteins that variously contribute to the modulation of intracellular second-messenger signaling kinetics. These many RGS proteins each interact with a specific set of second-messenger cascades and receptor types and exhibit tissue-specific expression patterns. Increasing evidence supports the contribution of RGS proteins, or their loss, in the pathogenesis of cardiovascular dysfunctions. This review summarizes the current understanding of the functional contributions of RGS proteins, particularly within the B/R4 family, in cardiovascular disorders of pregnancy including gestational hypertension, uterine artery dysfunction, and preeclampsia.

Prioritizing Functional Capacity as a Principal End Point for Therapies Oriented to Older Adults With Cardiovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care. Whereas cardiorespiratory function has long been applied by cardiologists as a measure of function that depended primarily on cardiac physiology, multiple other factors also contribute, usually with increasing bearing as age advances. Comorbidity, inflammation, mitochondrial metabolism, cognition, balance, and sleep are among the constellation of factors that bear on cardiorespiratory function and that become intricately entwined with cardiovascular health in old age. This statement reviews the essential physiology underlying functional capacity on systemic, organ, and cellular levels, as well as critical clinical skills to measure multiple realms of function (eg, aerobic, strength, balance, and even cognition) that are particularly relevant for older patients. Clinical therapeutic perspectives and patient perspectives are enumerated to clarify challenges and opportunities across the caregiving spectrum, including patients who are hospitalized, those managed in routine office settings, and those in skilled nursing facilities. Overall, this scientific statement provides practical recommendations and vital conceptual insights.

Minority stress and leukocyte gene expression in sexual minority men living with treated HIV infection.

Sexual minority (i.e., non-heterosexual) individuals experience poorer mental and physical health, accounted for in part by the additional burden of sexual minority stress occurring from being situated in a culture favoring heteronormativity. Informed by previous research, the purpose of this study was to identify the relationship between sexual minority stress and leukocyte gene expression related to inflammation, cancer, immune function, and cardiovascular function. Sexual minority men living with HIV who were on anti-retroviral medication, had viral load < 200 copies/mL, and had biologically confirmed, recent methamphetamine use completed minority stress measures and submitted blood samples for RNA sequencing on leukocytes. Differential gene expression and pathway analyses were conducted comparing those with clinically elevated minority stress (n = 18) and those who did not meet the clinical cutoff (n = 20), covarying reactive urine toxicology results for very recent stimulant use. In total, 90 differentially expressed genes and 138 gene set pathways evidencing 2-directional perturbation were observed at false discovery rate (FDR) < 0.10. Of these, 41 of the differentially expressed genes and 35 of the 2-directionally perturbed pathways were identified as functionally related to hypothesized mechanisms of inflammation, cancer, immune function, and cardiovascular function. The neuroactive-ligand receptor pathway (implicated in cancer development) was identified using signaling pathway impact analysis. Our results suggest several potential biological pathways for future work investigating the relationship between sexual minority stress and health.

Connexins and Pannexins in Vascular Function and Disease.

Connexins (Cxs) and pannexins (Panxs) are ubiquitous membrane channel forming proteins that are critically involved in many aspects of vascular physiology and pathology. The permeation of ions and small metabolites through Panx channels, Cx hemichannels and gap junction channels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. This review provides an overview of current knowledge with respect to the pathophysiological role of these channels in large arteries, the microcirculation, veins, the lymphatic system and platelet function. The essential nature of these membrane proteins in vascular homeostasis is further emphasized by the pathologies that are linked to mutations and polymorphisms in Cx and Panx genes.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.

Lncing epigenetic control of transcription to cardiovascular development and disease.

Transcriptional and epigenetic regulation is critical for proper heart development, cardiac homeostasis, and pathogenesis. Long noncoding RNAs have emerged as key components of the transcriptional regulatory pathways that govern cardiac development as well as stress response, signaling, and remodeling in cardiac pathologies. Within the past few years, studies have identified many long noncoding RNAs in the context of cardiovascular biology and have begun to reveal the key functions of these transcripts. In this review, we discuss the growing roles of long noncoding RNAs in different aspects of cardiovascular development as well as pathological responses during injury or disease. In addition, we discuss diverse mechanisms by which long noncoding RNAs orchestrate cardiac transcriptional programs. Finally, we explore the exciting potential of this novel class of transcripts as biomarkers and novel therapeutic targets for cardiovascular diseases.

Exercise Training and Epigenetic Regulation: Multilevel Modification and Regulation of Gene Expression.

Exercise training elicits acute and adaptive long term changes in human physiology that mediate the improvement of performance and health state. The responses are integrative and orchestrated by several mechanisms, as gene expression. Gene expression is essential to construct the adaptation of the biological system to exercise training, since there are molecular processes mediating oxidative and non-oxidative metabolism, angiogenesis, cardiac and skeletal myofiber hypertrophy, and other processes that leads to a greater physiological status. Epigenetic is the field that studies about gene expression changes heritable by meiosis and mitosis, by changes in chromatin and DNA conformation, but not in DNA sequence, that studies the regulation on gene expression that is independent of genotype. The field approaches mechanisms of DNA and chromatin conformational changes that inhibit or increase gene expression and determine tissue specific pattern. The three major studied epigenetic mechanisms are DNA methylation, Histone modification, and regulation of noncoding RNA-associated genes. This review elucidates these mechanisms, focusing on the relationship between them and their relationship with exercise training, physical performance and the enhancement of health status. On this chapter, we clarified the relationship of epigenetic modulations and their intimal relationship with acute and chronic effect of exercise training, concentrating our effort on skeletal muscle, heart and vascular responses, that are the most responsive systems against to exercise training and play crucial role on physical performance and improvement of health state.

Functional and physiopathological implications of TRP channels.

Transient Receptor Potential (TRP) channel proteins are a diverse family of proteins that are expressed in many organisms, tissues and cell types. TRP channels respond to a variety of stimuli, including light, mechanical or chemical stimuli, temperature, pH or osmolarity. In addition, several TRP family members have been identified as downstream molecules in the G protein-coupled receptor signaling pathway. TRP proteins are involved in a variety of cell functions both in non-excitable and excitable cells due to their diverse permeability to cations and their ability to modulate intracellular Ca2+ signaling. Emerging evidence suggests that TRP channel dysfunction significantly contributes to the physiopathology of a number of diseases, including cardiovascular, neurological, metabolic or neoplastic disorders. This review focuses on the implication of TRP proteins in the pathogenesis of some of the most prevalent disorders in human. We summarize the current findings regarding the role of TRP proteins in the development of cardiovascular disease, diabetes mellitus as well as diabetic complications, and tumorigenesis and present TRP proteins as targets of potential diagnostic and therapeutic strategies.

Genome-wide association studies and contribution to cardiovascular physiology.

The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology.

Polymorphism of dopamine transporter gene DAT1 and individual variability of defense cardiac response in humans.

We evaluated association of BP stress-reactivity on the model of cardiac defense response in 45-70-year-old men with variable number of tandem repeat polymorphism in genes encoding dopamine transporter protein (DAT1) and serotonin transporter protein (5-HTTLPR). It was found that individuals carrying long allele variant (l) of DAT1 gene (l/l: allele l homozygotes) in the genotype in comparison with short variant (s) carriers (heterozygous genotype l/s) demonstrate hyperreactive profiles of cardiovascular stress reactivity characterized by a significant increase in the amplitude and duration of long-latency BP components in cardiac defensive response.

An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model.

Investigating and understanding gene-environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia-hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia-hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia-hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.

Cardiovascular importance of the microRNA-23/27/24 family.

MicroRNAs (miRNAs) are a class of highly conserved, noncoding short RNA molecules that regulate gene expression on the post-transcriptional level. MiRNAs are involved in a variety of processes such as proliferation, differentiation, and apoptosis. Deregulated expression of miRNAs has been linked to the development of diseases including cardiovascular disorders. Recently, the miR-23/27/24 cluster has been shown to be involved in angiogenesis and endothelial apoptosis in cardiac ischemia and retinal vascular development. In the present review, we summarize and discuss the role and importance of the miRNA-23/27/24 cluster during cardiovascular angiogenesis. Moreover, we illustrate a novel therapeutic application of the miRNA-23/27/24 cluster in vascular disorders and ischemic heart disease.

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.

The hypoxia-inducible factors (HIFs; isoforms HIF-1α, HIF-2α, HIF-3α) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2α gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2α gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2α gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2α gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1α is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia.

Integration of metabolic and cardiovascular diurnal rhythms by circadian clock.

Understanding how the 24-hour blood-pressure rhythm is programmed has been one of the most challenging questions in cardiovascular research. The 24-hour blood-pressure rhythm is primarily driven by the circadian clock system, in which the master circadian pacemaker within the suprachiasmatic nuclei of the hypothalamus is first entrained to the light/dark cycle and then transmits synchronizing signals to the peripheral clocks common to most tissues, including the heart and blood vessels. However, the circadian system is more complex than this basic hierarchical structure, as indicated by the discovery that peripheral clocks are either influenced to some degree or fully driven by temporal changes in energy homeostasis, independent of the light entrainment pathway. Through various comparative genomic approaches and through studies exploiting mouse genetics and transgenics, we now appreciate that cardiovascular tissues possess a large number of metabolic genes whose expression cycle and reciprocally affect the transcriptional control of major circadian clock genes. These findings indicate that metabolic cycles can directly or indirectly affect the diurnal rhythm of cardiovascular function. Here, we discuss a framework for understanding how the 24-hour blood-pressure rhythm is driven by the circadian system that integrates cardiovascular and metabolic function.