Breast cancer chemotherapy vascular toxicity: A review of mediating mechanisms and exercise as a potential therapeutic

Breast cancer chemotherapy, although very potent against tumour tissue, results in significant cardiovascular toxicity. The focus of research in this area has been predominantly towards cardiotoxicity. There is limited evidence detailing the impact of such treatment on the vasculature despite its central importance within the cardiovascular system and resultant detrimental effects of damage and dysfunction. This review highlights the impact of chemotherapy for breast cancer on the vascular endothelium. We consider the most likely mechanisms of endothelial toxicity to be through direct damage and dysfunction of the endothelium. There are sharp consequences of these detrimental effects as they can lead to cardiovascular disease. However, there is potential for exercise to alleviate some of the vascular toxicity of chemotherapy, and the evidence for this is provided. The potential role of exercise in protecting against vascular toxicity is explained, highlighting the recent in-human and animal model exercise interventions. Lastly, the mediating mechanisms of exercise protection of endothelial health is discussed, focusing on the importance of exercise for endothelial health, function, repair, inflammation and hyperlipidaemia, angiogenesis, and vascular remodelling. These are all important counteracting measures against chemotherapy-induced toxicity and are discussed in detail.

Rho GTPase signalling networks in cancer cell transendothelial migration

Extravasation, the process by which tumor cells leave the circulation by transmigrating through the endothelium that lines blood vessel walls, is an essential step for metastasis towards distant organs. As such, reducing extravasation of cancer cells is a potential approach to inhibit metastasis. Rho GTPases are small signalling G-proteins that are central regulators of cytoskeleton dynamics, and thereby mediate several steps of the metastatic cascade, including invasion, migration, and extravasation of cancer cells. Additionally, RhoGTPase signalling networks regulate cancer cell-endothelial cell interactions and are involved in the disruption of the endothelial barrier function, allowing cancer cells to extravasate the underlying tissue. Thus, targeting Rho GTPase signalling networks may be an effective approach to inhibit extravasation and metastasis. In this review, the roles and regulation of Rho GTPase signalling networks in cancer cell extravasation will be discussed, both from a cancer cell and endothelial cell point of view.

The effect of absent blood flow on the zebrafish cerebral and trunk vasculature

The role of blood flow in vascular development is complex and context-dependent. In this study, we quantify the effect of the lack of blood flow on embryonic vascular development on two vascular beds, namely the cerebral and trunk vasculature in zebrafish. We perform this by analysing vascular topology, endothelial cell (EC) number, EC distribution, apoptosis, and inflammatory response in animals with normal blood flow or absent blood flow. We find that absent blood flow reduced vascular area and endothelial cell number significantly in both examined vascular beds, but the effect is more severe in the cerebral vasculature, and severity increases over time. Absent blood flow leads to an increase in non-EC-specific apoptosis without increasing tissue inflammation, as quantified by cerebral immune cell numbers and nitric oxide. Similarly, while stereotypic vascular patterning in the trunk is maintained, intra-cerebral vessels show altered patterning, which is likely to be due to vessels failing to initiate effective fusion and anastomosis rather than sprouting or path-seeking. In conclusion, blood flow is essential for cellular survival in both the trunk and cerebral vasculature, but particularly intra-cerebral vessels are affected by the lack of blood flow, suggesting that responses to blood flow differ between these two vascular beds.

Vascular dysfunction and pathology: focus on mechanical forces

The role of mechanical forces is emerging as a new player in pathophysiologic programming of the cardiovascular system. The ability of the cells to ‘sense’ mechanical forces does not relate only to perception of movement or flow, as intended traditionally, but also to the biophysical properties of the extracellular matrix, the geometry of the tissues and the force distribution inside them. This is also supported by the finding that cells can actively translate mechanical cues into discrete gene expression and epigenetic programming. In the present review we will contextualize these new concepts in the vascular pathologic programming.

MicroRNAs involved in Psoriasis and cardiovascular diseases

Psoriasis is a chronic inflammatory disease involving skin. Both genetic and environmental factors play a pathogenic role in psoriasis and contribute to the severity of the disease. Psoriasis, in fact, has been associated with different comorbidities such as diabetes, metabolic syndrome, gastrointestinal or kidney diseases, cardiovascular diseases (CVD), and cerebrovascular diseases (CeVD). Indeed, life expectancy in severe psoriasis is reduced by up to 5 years due to CVD and CeVD. Moreover, patients with severe psoriasis have a higher prevalence of traditional cardiovascular (CV) risk factors, including dyslipidaemia, diabetes, smoking, and hypertension. Further, systemic inflammation is associated with oxidative stress increase and induces endothelial damage and atherosclerosis progression. Different microRNAs have been already described in psoriasis, both in the skin tissues and in the blood flow, to play a role in the progression of disease. In this review we will summarize and discuss the most important miRNAs that play a role in psoriasis and have been also linked to CVD.

SARS-CoV-2 and endothelial cell interaction in COVID-19: molecular perspectives

SARS-CoV-2 is the agent responsible for the coronavirus disease (COVID-19), which has been declared a pandemic by the World Health Organization. The clinical evolution of COVID-19 ranges from asymptomatic infection to death. Older people and patients with underlying medical conditions, particularly diabetes, cardiovascular and chronic respiratory diseases are more susceptible to develop severe forms of COVID-19. Significant endothelial damage has been reported in COVID-19 and growing evidence supports the key pathophysiological role of this alteration in the onset and the progression of the disease. In particular, the impaired vascular homeostasis secondary to the structural and functional damage of the endothelium and its main component, the endothelial cells, contributes to the systemic proinflammatory state and the multiorgan involvement observed in COVID-19 patients. This review summarizes the current evidence supporting the proposition that the endothelium is a key target of SARS-CoV-2, with a focus on the molecular mechanisms involved in the interaction between SARS-CoV-2 and endothelial cells.

Bio-chemo-mechanics of the thoracic aorta

The pathophysiology of thoracic aortic aneurysm and dissection is poorly understood, despite high mortality. An evidence review was conducted to examine the biomechanical, chemical and genetic factors involved in thoracic aortic pathology. The composition of connective tissue and smooth muscle cells can mediate important mechanical properties that allow the thoracic aorta to withstand and transmit pressures. Genetic syndromes can affect connective tissue and signalling proteins that interrupt smooth muscle function, leading to tissue failure. There are complex interplaying factors that maintain thoracic aortic function in health and are disrupted in disease, signifying an area for extensive research.

Aging- and gender-related modulation of RAAS: potential implications in COVID-19 disease

Coronavirus disease 2019 (COVID-19) is a new infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is frequently characterized by a marked inflammatory response with severe pneumonia and respiratory failure associated with multiorgan involvement. Some risk factors predispose patients to develop a more severe infection and to an increased mortality; among them, advanced age and male gender have been identified as major and independent risk factors for COVID-19 poor outcome. The renin-angiotensin-aldosterone system (RAAS) is strictly involved in COVID-19 because angiotensin converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 and also converts pro-inflammatory angiotensin (Ang) II into anti-inflammatory Ang(1–7). In this review, we have addressed the effect of aging and gender on RAAS with emphasis on ACE2, pro-inflammatory Ang II/Ang II receptor 1 axis and anti-inflammatory Ang(1–7)/Mas receptor axis.

The Ageing Endothelium

Cellular senescence is now recognised as one of the hallmarks of ageing. Herein, we examine current findings on senescence of the vascular endothelium and its impacts on age-related vascular diseases. Endothelial senescence can result in systemic metabolic changes, implicating senescence in chronic diseases such as diabetes, obesity and atherosclerosis. Senolytics, drugs that eliminate senescent cells, afford new therapeutic strategies for control of these chronic diseases.

MicroRNA-145 targets in cancer and the cardiovascular system: evidence for common signaling pathways

miRNAs are small regulatory RNAs which govern gene expression post-transcriptionally by primarily binding to the 3'-UTR of mRNA target genes. miR-145 is a well-studied miRNA that has been implicated in controlling a range of biological processes. miR-145 is expressed in a variety of tissues and cell types and acts as a tumor-suppressor by regulating target gene signaling pathways involved in different aspects of tumor growth and progression. There is also strong evidence that highlights the important functions of miR-145 in the cardiovascular system. Here, we review the mechanisms of miR-145 in tumorigenesis and cancer progression and compare and contrast with the roles of miR-145 in cardiovascular development and disease. We discuss the important targets of miR-145 in cancer and their possible link to the cardiovascular system.