Cardiovascular diseases are the leading cause of mortality and morbidity worldwide and account for more than 17.9 million deaths (World Health Organization report). Hypertension and aging are two major risk factors for the development of cardiac structural and functional abnormalities. Hypertension, or elevated blood pressure, if left untreated can result in myocardial hypertrophy leading to heart failure (HF). Left ventricular hypertrophy consequent to pressure overload is recognized as the most important predictor of congestive HF and sudden death. The pathological changes occurring during hypertensive heart disease are very complex and involve many cellular and molecular alterations. In contrast, the cardiac changes that occur with aging are a slow but life-long process and involve all of the structural components in the heart and vasculature. However, these structural changes in the cardiovascular system lead to alterations in overall cardiac physiology and function. The pace at which these pathophysiological changes occur varies between individuals owing to many genetic and environmental risk factors. This review highlights the molecular mechanisms of cardiac structural and functional alterations associated with hypertension and aging.

RNA‐binding proteins like human antigen R (HuR) are key regulators in post‐transcriptional control of gene expression in several pathophysiological conditions. Diabetes adversely affects monocyte/macrophage biology and function. It is not known whether diabetic milieu affects cellular/exosome‐HuR and its implications on cardiac inflammation and fibrosis. Here, we evaluate in vitro and in vivo effects of diabetic milieu on macrophage cellular/exosome‐HuR, alterations in intercellular cross talk with fibroblasts, and its impact on cardiac remodeling. Human failing hearts show higher HuR levels. Diabetic milieu activates HuR expression in cardiac‐ and cultured bone marrow‐derived macrophages (BMMØ) and stimulates HuR nuclear‐to‐cytoplasmic translocation and exosome transfer. Exosomes from macrophages exposed to diabetic milieu (high glucose or db/db mice) significantly increase inflammatory and profibrogenic responses in fibroblast (in vitro) and cardiac fibrosis in mice. Intriguingly, Exo‐HuR deficiency (HuR knockdown in macrophage) abrogates the above effects. In diabetic mice, macrophage depletion followed by reconstitution with BMMØ‐derived HuR‐deficient exosomes inhibits angiotensin II‐induced cardiac fibrosis response and preserves left ventricle function as compared to control‐exosome administration. To the best of our knowledge, this is the first study to demonstrate that diabetes activates BMMØ HuR expression and its transfer into exosome. The data suggest that HuR might be targeted to alleviate macrophage dysfunction and pathological fibrosis in diabetes.

Rationale: After myocardial ischemic injury, improper phagocytic clearance of dying cardiac cells and the ensuing lack of inflammation resolution results in adverse cardiac remodeling and dysfunction that might lead to heart failure. Therefore, therapeutic strategies to ameliorate immune cell phagocytic function are critical for augmenting cardiac repair after injury. Objective: To determine whether mesenchymal stem cell–derived exosomes (MSC-Exos) act as opsonin for apoptotic cells or trigger eat-me phagocytic signaling in resident/recruited phagocytes after myocardial ischemic injury. Methods and Results: We evaluated MSC-Exo–mediated opsonization of apoptotic cardiomyocytes and in vitro and in vivo effects of MFGE8 (milk fat globule epidermal growth factor-factor VIII)-deficient mouse MSC-Exo on macrophage engulfment of apoptotic cardiomyocytes and its implications on cardiac remodeling, repair, and function. Microscopy and FACS analyses show that opsonization of apoptotic cardiomyocytes with MSC-Exo enhances their engulfment by macrophages. Furthermore, preincubation of macrophages with MSC-Exo reprogrammed the signaling pathways involved in phagocytosis and expression of proreparative cytokines. Protein analysis of MSC-Exo reveals expression of MFGE8—a glycoprotein that bridges externalized phosphatidylserine on the apoptotic cell surface to αVβ3 or αVβ5 integrins on the phagocyte. Most intriguingly, siRNA inhibition of MFGE8 significantly reduced the MSC-Exo–mediated augmentation of dead cell engulfment, associated signaling, and proreparative phenotype. After myocardial ischemic injury, intramyocardial administration of MSC-Exo increases macrophage uptake of apoptotic bodies in the border zone of infarct and is associated with reduced proinflammatory response, increase in neovascularization, lower infarct size, and an improvement in cardiac function and MFGE8-deficient MSC-Exo administration failed to protect mice against myocardial infarction. Conclusions: Our data demonstrate that exosome-associated MFGE8 on one hand enhances opsonization of dead cells and on the other activates phagocytic signaling, thus augmenting removal of apoptotic cells, resolution of inflammation, and, therefore, efficient cardiac recovery after injury.

Extracellular vesicles (EVs) are nanosized lipid bilayer-delimited particles released from cells that mediate intercellular communications and play a pivotal role in various physiological and pathological processes. Subtypes of EVs may include plasma membrane ectosomes or microvesicles and endosomal origin exosomes, although functional distinctions remain unclear. EVs carry cargo proteins, nucleic acids (RNA and DNA), lipids, and metabolites. By presenting or transferring this cargo to recipient cells, EVs can trigger cellular responses. We summarize contemporary understanding of EV biogenesis, composition, and function, with an emphasis on the role of EVs in the cardiovascular system. In addition, we outline the functional relevance of EVs in cardiovascular pathophysiology, further highlighting their potential for diagnostic and therapeutic applications.

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role in cell–cell communications. Exosomes have evolved as potential biomarkers for aging-related diseases. Aging, a physiological process, involves a progressive decline of function of organs with a loss of homeostasis and increasing probability of illness and death. The review focuses on the classic view of exosome biogenesis, biology, and age-associated changes. Owing to their ability to transport biological information among cells, the review also discusses the interplay of senescent cell-derived exosomes with the aging process, including the susceptibility of the aging population to COVID-19 infections.

Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms—including pain, bleeding, disfigurement, and functional defects of vital organs—in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.