Current Opinion in Physiology

The lethality of heart failure (HF), particularly in the context of post-acute sequelae SARS-CoV-2 infection (PASC)-related myocarditis, necessitates the discovery of the cellular pathways implicated in cardiovascular disease (CVD). We summarize the signaling mechanisms of the catecholamine-binding β-adrenergic receptors (β-ARs), with an emphasis on the role of β-arrestins. β-ARs, a subset of G protein-coupled receptors (GPCRs), canonically propagate signals through heterotrimeric G proteins...

High endothelial venules (HEVs), high walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (aka tertiary lymphoid organs). HEV heterogeneity exists between various lymphoid organs in their expression of peripheral node addressin (PNAd) and mucosal vascular addressin adhesion molecule 1(MAdCAM-1). Transcriptomic analyses reveal extensive heterogeneity, plasticity, and regulation of HEV gene expression in ontogeny, acute inflammation, and chronic inflammation within and between lymphoid organs...

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is diagnosed by the presence of two of the following three characteristics: hyperandrogenemia and/or hyperandrogenism, oligo/amenorrhea, and polycystic ovarian morphology. PCOS is associated with reproductive and non-reproductive complications, including obesity, insulin resistance and diabetes, dyslipidemia, and increased blood pressure. There is an urgent need for biomarkers that address both the reproductive and non-reproductive aspects of this complex syndrome...

The complex and hierarchical vascular network of arteries, veins, and capillaries features considerable endothelial heterogeneity, yet the regulatory pathways directing arteriovenous specification, differentiation, and identity are still not fully understood. Recent advances in analysis of endothelial-specific gene-regulatory elements, single-cell RNA sequencing, and cell lineage tracing have both emphasized the importance of transcriptional regulation in this process and shed considerable light on the mechanism and regulation of specification within the endothelium...

Endothelial caveolae are essential for a wide range of physiological processes and have emerged as key players in vascular biology. Our understanding of caveolar biology in endothelial cells has expanded dramatically since their discovery revealing critical roles in mechanosensation, signal transduction, eNOS regulation, lymphatic transport, and metabolic disease progression. Furthermore, caveolae are involved in the organization of membrane domains, regulation of membrane fluidity, and endocytosis which contribute to endothelial function and integrity...

Myocarditis is frequently caused by viral infections, but animal models that closely resemble human disease suggest that virus-triggered autoimmune disease is the most likely cause of myocarditis. Myocarditis is a rare condition that occurs primarily in men under age 50. The incidence of myocarditis rose at least 15x during the COVID-19 pandemic from 1-10 to 150-400 cases/100,000 individuals, with most cases occurring in men under age 50. COVID-19 vaccination was also associated with rare cases of myocarditis primarily in young men under 50 years of age with an incidence as high as 50 cases/100,000 individuals reported for some mRNA vaccines...

The vasculature is characterized by a thin cell layer that comprises the inner wall of all blood vessels, the continuous endothelium. Endothelial cells can also be found in the eye's cornea. And even though cornea and vascular endothelial (VE) cells differ from each other in structure, they both function as barriers and express similar junctional proteins such as the adherens junction VE-cadherin and tight-junction member claudin-5. How these barriers are controlled to maintain the barrier and thereby its integrity is of major interest in the development of potential therapeutic targets...

A poor uterine environment causes changes in fetal development that affect the health of offspring long-term. Although there are multiple pathways that contribute to the development of cardiovascular and neurological disease, low birth weight or fetal growth restriction (FGR) predisposes offspring to these diseases. There is a link between fetal exposure to adverse influences and hypertension later in life. Many epidemiological studies support the link between fetal life and the risk of disease later in life...

Endothelial-to-mesenchymal transition (EndMT) is a physiological process that is equally important during development and under certain pathological conditions in adult tissues. The last decade has witnessed a remarkable explosion of information about EndMT from molecular mechanisms responsible for its development to its role in various disease processes. The emerging picture is that of a complex set of interactions that underly pathophysiological basis of some of the most deadly and intractable diseases. This mini review brings together recent advances and attempts to present a unified view of this complex field...

Endothelial cell (EC) dysfunction is a characteristic complication of coronavirus-19 (COVID-19). This review discusses the role of the endothelium during the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a focus on different vascular beds, possible routes of infectivity and the impact of EC dysfunction across multiple organ systems. It is now known that COVID-19 disease elicits a distinct transcriptomic and molecular profile that is different to other viral infections, such as Influenza A (H1N1)...

Preeclampsia (PE) is a multisystem obstetric disorder that affects 2-10% of pregnancies worldwide and it is a leading cause of maternal and fetal morbidity and mortality. The etiology of PE development is not clearly delineated, but since delivery of the fetus and placenta often leads to symptom resolution in the most cases of PE, it is hypothesized that the placenta is the inciting factor of the disease. Current management strategies for PE focus on treating the maternal symptoms to stabilize the mother in an attempt to prolong the pregnancy...

Sex recorded at birth, gender identity, and feminizing gender-affirming hormone therapy (fGAHT) likely contribute to cardiovascular disease (CVD) risk in transgender women. Understanding the interplay of these factors is necessary for the provision of safe, affirming, and lifesaving care. Among transgender women taking fGAHT, data show increases in CVD mortality and rates of myocardial infarction, stroke, and venous thromboembolism compared to reference populations, depending on study design and comparators...

Macroautophagy, herein referred to as autophagy, has long been implicated in the pathophysiology of neurodegenerative diseases. However, an incomplete understanding of how autophagy contributes to disease pathogenesis has limited progress in acting on this potential target for the development of disease modifying therapeutics. Research in the past few decades has revealed that autophagy plays a specialized role in the synapse, a site of early dysfunction in multiple neurodegenerative diseases. In this review we discuss the evidence suggesting that inadequate autophagy at the synapse may contribute to neurodegeneration, and why the functions of autophagy may be particularly relevant for synaptic function...

Preeclampsia remains a major health concern for mother and child. Yet, treatment options remain limited to early delivery. Placental dysfunction in preeclampsia occurs in response to an increase in oxidative stress and inflammatory cytokines with vasoactive and anti-angiogenic factors contributing to impaired maternal and fetal health. Moreover, recent studies indicate a potential role for epigenetic mediators in the pathophysiology of placental ischemia. Numerous animal models are utilized to explore the pathogenesis of preeclampsia and fetal growth restriction...

Hair cells of the mammalian cochlea are specialized mechanosensory cells that convert mechanical stimuli into electrical signals to initiate the neuronal responses that lead to the perception of sound. The mechanoelectrical transduction (MET) machinery of cochlear hair cells is a multimeric protein complex that consists of the pore forming subunits of the MET channel and several essential accessory subunits that are crucial to regulate channel function and render the channel mechanically sensitive. Mutations have been discovered in the genes that encode all known components of the MET machinery...

Exercise leads to numerous beneficial whole-body effects and can protect against the development of obesity, cardiometabolic, and neurodegenerative diseases. Recent studies have highlighted the importance of inter-organ crosstalk with a focus on secretory factors that mediate communication among organs, including adipose tissue and the heart. Studies investigating the effects of exercise on brown adipose tissue (BAT) and white adipose tissue (WAT) demonstrated that adipokines are released in response to exercise and act on the heart to decrease inflammation, alter gene expression, increase angiogenesis, and improve cardiac function...

Lysosomes are subjected to physiological and patho-physiological insults over the course of their life cycle and are accordingly repaired or recycled. Lysophagy, the selective degradation of lysosomes via autophagy, occurs upon unrepairable lysosomal membrane rupture; galectins bind to glycosylated macromolecules in the lysosome lumen, orchestrating a series of cellular responses to promote autophagic recycling of damaged lysosomes and transcriptional upregulation of lysosomal genes. Damaged lysosomes are ubiquitylated, resulting in the recruitment of ubiquitin-binding autophagy receptors, which promote assembly of an autophagosome around damaged lysosomes for delivery to healthy lysosomes for degradation...

Dynamin-related protein 1 (Drp1), the master regulator of mitochondrial division (MD), interacts with the cytoskeletal elements, namely filamentous actin (F-actin), microtubules (MT), and septins that coincidentally converge at MD sites. However, the mechanistic contributions of these critical elements to, and their cooperativity in, MD remain poorly characterized. Emergent data indicate that the cytoskeleton plays combinatorial modulator, mediator, and effector roles in MD by 'priming' and 'channeling' Drp1 for mechanoenzymatic membrane remodeling...

Cardiotoxicity, or the development of unwarranted cardiovascular side-effects of oncologic therapies, can involve all aspects of cardiovascular disease. The development of cardiac fibrosis is a dreaded complication that leads to cardiac mechanical dysfunction, tachyarrhythmias, and an increase in cardiovascular mortality. This review details established and putative mechanisms leading to fibroblast activation, myofibroblast transdifferentiation, and the development of replacement or interstitial cardiac fibrosis as a consequence of cancer treatments...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) orchestrates host factors to remodel endomembrane compartments for various steps of the infection cycle. SARS-CoV-2 also intimately intersects with the catabolic autophagy pathway during infection. In response to virus infection, autophagy acts as an innate defensive system by delivering viral components/particles to lysosomes for degradation. Autophagy also elicits antiviral immune responses. SARS-CoV-2, like other positive-stranded RNA viruses, has evolved various mechanisms to escape autophagic destruction and to hijack the autophagic machinery for its own benefit...