Significance A layer of fat surrounds the heart in most mammals, including humans. The biology of this tissue has been speculated for centuries, but never subjected to experimental analysis because ...common experimental model species are thought to not have this tissue. In this study, we show that rodents have cardiac fat, albeit in a very specific location in the heart. We implicate the origin of this tissue from the epicardium (the outer epithelium of the heart) and the underlying mechanisms that account for its derivation. By comparing human and mouse epicardial cells, we provide an explanation for the prominent species differences in the presence and amount of cardiac adipose tissue.
The hearts of many mammalian species are surrounded by an extensive layer of fat called epicardial adipose tissue (EAT). The lineage origins and determinative mechanisms of EAT development are unclear, in part because mice and other experimentally tractable model organisms are thought to not have this tissue. In this study, we show that mouse hearts have EAT, localized to a specific region in the atrial–ventricular groove. Lineage analysis indicates that this adipose tissue originates from the epicardium, a multipotent epithelium that until now is only established to normally generate cardiac fibroblasts and coronary smooth muscle cells. We show that adoption of the adipocyte fate in vivo requires activation of the peroxisome proliferator activated receptor gamma (PPARγ) pathway, and that this fate can be ectopically induced in mouse ventricular epicardium, either in embryonic or adult stages, by expression and activation of PPARγ at times of epicardium–mesenchymal transformation. Human embryonic ventricular epicardial cells natively express PPARγ, which explains the abundant presence of fat seen in human hearts at birth and throughout life.
Maturation of a vascular plexus is a critical and yet incompletely understood process in organ development, and known maturation factors act universally in all vascular beds. In this study, we show ...that CXCL12 is an organ-specific maturation factor of particular relevance in coronary arterial vasculature. In vitro, CXCL12 does not influence nascent vessel formation, but promotes higher-order complexity of preinitiated vessels. In the heart, CXCL12 is expressed principally by the epicardium, and its receptor CXCR4 is expressed by coronary endothelial cells. CXCL12 is not a chemotactic signal for endothelial cell migration, but rather acts in a paracrine manner to influence the maturation of the coronary vascular plexus. Mutants in CXCL12 signaling show an excess of immature capillary chains and a selective failure in arterial maturation, and become leaky with the onset of coronary perfusion. Failed maturation of the coronary system explains the late-gestation lethality of these mutants.
•CXCL12 is a vascular maturation factor important in coronary artery development•CXCL12 acts in an organ-specific and paracrine manner•Defective coronary formation explains late-gestation lethality of CXCL12 mutants•The sinus venosus is the primary origin of embryonic coronary endothelium
Cavallero et al. show that CXCL12 is an organ-specific vascular maturation factor that promotes higher-order complexity of preinitiated vessels. In the heart, deficiency in CXCL12/CXCR4 signaling results in a poorly formed coronary system and insufficient myocardial perfusion, and accounts for late-gestation lethality seen in these mutants.
Secreted factors from the epicardium are believed to be important in directing heart ventricular cardiomyocyte proliferation and morphogenesis, although the specific factors involved have not been ...identified or characterized adequately. We found that IGF2 is the most prominent mitogen made by primary mouse embryonic epicardial cells and by a newly derived immortalized mouse embryonic epicardial cell line called MEC1. In vivo, Igf2 is expressed in the embryonic mouse epicardium during midgestation heart development. Using a whole embryo culture assay in the presence of inhibitors, we confirmed that IGF signaling is required to activate the ERK proliferation pathway in the developing heart, and that the epicardium is required for this response. Global disruption of the Igf2 gene, or conditional disruption of the two IGF receptor genes Igf1r and Insr together in the myocardium, each resulted in a significant decrease in ventricular wall proliferation and in ventricular wall hypoplasia. Ventricular cardiomyocyte proliferation in mutant embryos was restored to normal at E14.5, concurrent with the establishment of coronary circulation. Our results define IGF2 as a previously unexplored epicardial mitogen that is required for normal ventricular chamber development.
Wall shear stress (WSS) contributes to the mechanotransduction underlying microvascular development and regeneration. Using computational fluid dynamics, we elucidated the interplay between WSS and ...vascular remodelling in a zebrafish model of tail amputation and regeneration. The transgenic
(
;
) zebrafish line was used to track the three-dimensional fluorescently labelled vascular endothelium for post-image segmentation and reconstruction of the fluid domain. Particle image velocimetry was used to validate the blood flow. Following amputation to the dorsal aorta and posterior cardinal vein (PCV), vasoconstriction developed in the dorsal longitudinal anastomotic vessel (DLAV) along with increased WSS in the proximal segmental vessels (SVs) from amputation. Angiogenesis ensued at the tips of the amputated DLAV and PCV where WSS was minimal. At 2 days post amputation (dpa), vasodilation occurred in a pair of SVs proximal to amputation, followed by increased blood flow and WSS; however, in the SVs distal to amputation, WSS normalized to the baseline. At 3 dpa, the blood flow increased in the arterial SV proximal to amputation and through anastomosis with DLAV formed a loop with PCV. Thus, our
modelling revealed the interplay between WSS and microvascular adaptation to changes in WSS and blood flow to restore microcirculation following tail amputation.
Complementary to mainstream cardiac imaging modalities for preclinical research, photoacoustic computed tomography (PACT) can provide functional optical contrast with high imaging speed and ...resolution. However, PACT has not been demonstrated to reveal the dynamics of whole cardiac anatomy or vascular system without surgical procedure (thoracotomy) for tissue penetration. Here, we achieved non-invasive imaging of rat hearts using the recently developed three-dimensional PACT (3D-PACT) platform, demonstrating the regulated illumination and detection schemes to reduce the effects of optical attenuation and acoustic distortion through the chest wall; thereby, enabling unimpeded visualization of the cardiac anatomy and intracardiac hemodynamics following rapidly scanning the heart within 10 s. We further applied 3D-PACT to reveal distinct cardiac structural and functional changes among the healthy, hypertensive, and obese rats, with optical contrast to uncover differences in cardiac chamber size, wall thickness, and hemodynamics. Accordingly, 3D-PACT provides high imaging speed and nonionizing penetration to capture the whole heart for diagnosing the animal models, holding promises for clinical translation to cardiac imaging of human neonates.
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of cardiometabolic diseases in overweight individuals. While liver biopsy is the current gold standard to diagnose NAFLD and ...magnetic resonance imaging (MRI) is a non-invasive alternative still under clinical trials, the former is invasive and the latter costly. We demonstrate electrical impedance tomography (EIT) as a portable method for detecting fatty infiltrate. We enrolled 19 overweight subjects to undergo liver MRI scans, followed by EIT measurements. The MRI images provided the a priori knowledge of the liver boundary conditions for EIT reconstruction, and the multi-echo MRI data quantified liver proton-density fat fraction (PDFF%) to validate fat infiltrate. Using the EIT electrode belts, we circumferentially injected pairwise current to the upper abdomen, followed by acquiring the resulting surface-voltage to reconstruct the liver conductivity. Pearson's correlation analyses compared EIT conductivity or MRI PDFF with body mass index, age, waist circumference, height, and weight variables. We reveal that the correlation between liver EIT conductivity or MRI PDFF with demographics is statistically insignificant, whereas liver EIT conductivity is inversely correlated with MRI PDFF (R = -0.69, p = 0.003, n = 16). As a pilot study, EIT conductivity provides a portable method for operator-independent and cost-effective detection of hepatic steatosis.
The involvement of natriuretic peptides was studied during the hypertrophic remodeling transition mediated by sequential exposure to chronic hemodynamic overload. We induced hypertension in rats by ...pressure (renovascular) or volume overload (DOCA-salt) during 6 and 12 weeks of treatment. We also studied the consecutive combination of both models in inverse sequences: RV 6 weeks/DS 6 weeks and DS 6 weeks/RV 6 weeks. All treated groups developed hypertension. Cardiac hypertrophy and left ventricular ANP gene expression were more pronounced in single DS than in single RV groups. BNP gene expression was positively correlated with left ventricular hypertrophy only in RV groups, while ANP gene expression was positively correlated with left ventricular hypertrophy only in DS groups. Combined models exhibited intermediate values between those of single groups at 6 and 12 weeks. The latter stimulus associated to the second applied overload is less effective than the former to trigger cardiac hypertrophy and to increase ANP and BNP gene expression. In addition, we suggest a correlation of ANP synthesis with volume overload and of BNP synthesis with pressure overload-induced hypertrophy after a prolonged treatment. Volume and pressure overload may be two mechanisms, among others, involved in the differential regulation of ANP and BNP gene expression in hypertrophied left ventricles. Plasma ANP levels reflect a response to plasma volume increase and volume overload, while circulating BNP levels seem to be regulated by cardiac BNP synthesis and ventricular hypertrophy.
Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is thought to be the primary driver for the increasingly recognized thrombotic ...complications in coronavirus disease 2019 patients, potentially due to the SARS‐CoV‐2 Spike protein binding to the human angiotensin‐converting enzyme 2 (hACE2). Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS‐CoV‐2 infection. As a result, cases of thrombotic events are reported following vaccination. Although vaccines are generally considered safe, due to genetic heterogeneity, age, or the presence of comorbidities in the population worldwide, the prediction of severe adverse outcome in patients remains a challenge. To elucidate Spike proteins underlying patient‐specific‐vascular thrombosis, the human microcirculation environment is recapitulated using a novel microfluidic platform coated with human endothelial cells and exposed to patient specific whole blood. Here, the blood coagulation effect is tested after exposure to Spike protein in nanoparticles and Spike variant D614G in viral vectors and the results are corroborated using live SARS‐CoV‐2. Of note, two potential strategies are also examined to reduce blood clot formation, by using nanoliposome‐hACE2 and anti‐Interleukin (IL) 6 antibodies.
SARS‐CoV‐2 infection drives the increasingly recognized thrombotic complications in COVID‐19 patients, potentially due to the SARS‐CoV‐2 Spike protein binding to human angiotensin‐converting enzyme 2. Vaccination therapies that are spike‐based can lead to a similar outcomes. Endothelialized channels exposed to patient specific blood in microfluidic platforms can be used to rapidly test for blood coagulation, predicting thrombotic events.
Air pollution is a rising public health issue worldwide. Cumulative epidemiological and experimental studies have shown that exposure to air pollution such as particulate matter (PM) is linked with ...increased hospital admissions and all-cause mortality. While previous studies on air pollution mostly focused on the respiratory and cardiovascular effects, emerging evidence supports a significant impact of air pollution on the gastrointestinal (GI) system. The gut is exposed to PM as most of the inhaled particles are removed from the lungs to the GI tract via mucociliary clearance. Ingestion of contaminated food and water is another common source of GI tract exposure to pollutants. Recent studies have associated air pollution with intestinal diseases, including appendicitis, colorectal cancer, and inflammatory bowel disease. In addition to the liver and adipose tissue, intestine is an important organ system for lipid metabolism, and the intestinal redox lipids might be tightly associated with the intestinal and systematic inflammation. The gut microbiota modulates lipid metabolism and contributes to the initiation and development of intestinal disease including inflammatory bowel disease. Recent data support microbiome implication in air pollution-mediated intestinal and systematic effects. In this review, the associations between air pollution and intestinal diseases, and the alterations of intestinal lipidome and gut microbiome by air pollution are highlighted. The potential mechanistic aspects underlying air pollution-mediated intestinal pathology will also be discussed.
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•Air pollution exposure is associated with the incidence of intestinal disease.•Air pollution promotes the production of pro-inflammatory oxidative lipids.•Air pollution alters the composition/diversity of gut microbiota.•Air pollution-mediated alterations of microbiome might affect lipid metabolism.
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