Current Opinion in Physiology最新文献

The lethality of heart failure, particularly in the context of post-acute sequelae SARS-CoV-2 infection-related myocarditis, necessitates the discovery of the cellular pathways implicated in cardiovascular disease. 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. However, since their discovery in the late 1980s, β-arrestins have been shown to both (i) quench G protein signaling and (ii) initiate their own independent signaling cascades, which is influenced by posttranslational modifications. β-arrestin-biased agonism by the beta-blocker carvedilol and its allosteric modulation can serve a cardioprotective role. The increasingly labyrinthine nature of GPCR signaling suggests that ligand-dependent β-AR signaling, either stimulated by an agonist or blocked by an antagonist, is selectively enhanced or suppressed by allosteric modulations, which are orchestrated by novel drugs or endogenous posttranslational modifications.

The average lifespan of humans is increasing worldwide, and the percentage of older adults is substantially growing. The adrenergic system is a crucial determinant for the cardiovascular homeostasis during aging. In this short review, we discuss the new insights that emerged concerning the role of adrenergic receptors and relative signaling in the aging of the heart and vasculature with particular emphasis on molecular mechanisms involved. We also examine specific therapeutic interventions that modulate the adrenergic system feasibly counteracting and delaying age-induced pathophysiological changes in cardiovascular function and structure.

Adrenergic receptors (AR) are essential regulators of vascular physiology and are largely used as pharmacological targets. This chapter will review the main roles of the vascular AR in both the endothelium and vascular smooth muscle. We will discuss the ability of ARs to regulate key functions in endothelial and smooth muscle cells and their involvement in several pathologic conditions such as hypertension, atherosclerosis, and heart failure.

Cancer progression involves complex interactions between tumor cells and the surrounding microenvironment. Chronic psychosocial stress and sympathetic nervous system activation lead to abnormal catecholamine release, impacting tumor cells directly and indirectly and fuelling cancer-promoting effects. However, the same adrenergic Receptor (AR) that mediate these effects could also convey exercise-related beneficial changes. Epidemiological studies show conflicting associations between stress, AR inhibitors, and breast cancer (BC) metastatic progression. Adrenergic sympathetic stress triggers sustained inflammatory and hypoxic-related signaling pathways, alters function and distribution of immune cell populations, and remodels blood vessels, leading to immunosuppression and premetastatic site formation. Activated AR initiate feedback loops with tyrosine kinase receptors and chemokine receptors, affecting stem-related transcription factors, pro-inflammatory mediators, angiogenic factors, and energy metabolism regulators, promoting tumor growth and invasion. Understanding molecular mechanisms of agonistic and antagonistic AR ligands and crosstalk with other signaling pathways is crucial for developing effective therapies targeting adrenergic-driven BC progression.

Angiogenesis, the process of building new vessels, is important in physiology. In addition, it is involved in different pathologies, including cancers, ischemia, macular degeneration and inflammatory bowel disease. The regulation of angiogenesis is multifaceted and according to recent data includes transcriptional modulation by enhancers and non-coding RNAs as well as post-transcriptional regulation by microRNAs. In this review, we highlight recent findings in this field that relate both to physiological and pathological angiogenesis and discuss the effects on key angiogenic factors.

To survive, all organisms must detect and respond to mechanical cues in their environment. Cells are subjected to a plethora of mechanical forces, such as hydrostatic pressure, cell-cell contact, stretch, compression, and shear stress. Mechanosensitive (MS) membrane proteins have evolved across all life kingdoms to sense and respond to forces in the membrane. Bacterial MS ion channels provide a blueprint for understanding the fundamental mechanisms that underpin cellular responses to mechanical signals. Recently, the identification of eukaryotic force transducers, which includes membrane proteins other than channels, has led to the recognition of common structural hallmarks and unified biophysical mechanisms that could potentially link these diverse proteins. Accumulating evidence suggests G protein-coupled receptors (GPCRs) are candidates for pressure sensing in mammals. This review summarises the current knowledge on MS GPCRs, describes the tools used to assess their mechanosensitivity, and aims to highlight the key characteristics that link these receptors to established mechanosensors.

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 coronavirus disease 2019 (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. Sex differences in the immune response to COVID-19 are virtually identical to the mechanisms known to drive sex differences in myocarditis pre-COVID based on clinical studies and animal models. The many similarities between COVID-19 vaccine-associated myocarditis to COVID-19 myocarditis and non-COVID myocarditis suggest common immune mechanisms drive disease.

This review examines how the experience of being a parent affects hippocampal plasticity throughout the lifespan, in both male and female rodents. The hippocampus is a unique region capable of producing new neurons throughout adulthood in numerous mammals. When transitioning into parenthood, there is a significant impact on hippocampal neurogenesis and other forms of plasticity in female and male rodents. However, research on the regulation and functional implications (such as cognitive abilities and anxiety regulation) is limited and mixed. Studies have been conducted across sexes, ages, and species. The effects of motherhood on the hippocampus are well-documented in monoparental laboratory rats, while research on fatherhood is more limited. Biparental species provide an opportunity to study this experience in both sexes. We review the current knowledge and propose future research questions to increase our understanding of the short- and long-term consequences of parenthood in both sexes.

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. Additionally, recent advances highlight the impact of caveolae-mediated signaling pathways on vascular homeostasis and pathology. Together, the diverse roles of caveolae discussed here represent a breadth of cellular functions presenting caveolae as a defining feature of endothelial form and function. In light of these new insights, targeting caveolae may hold potential for the development of novel therapeutic strategies to treat a range of vascular diseases.