Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the “epigenetic landscape” in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction, and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.
Sarah Costantino, Shafeeq A Mohammed, Samuele Ambrosini and Francesco Paneni
The endothelial barrier dysfunction, is the hallmark of inflammatory lung disease, including Acute Lung Injury and Acute Respiratory Distress Syndrome. The purpose of the present editorial is to emphasize on recent advances in the corresponding field, as it relates to P53. This tumor suppressor has been shown to enhance the vascular barrier integrity via distinct molecular pathways, and to mediate the protective effects of the heat shock protein 90 inhibitors; and growth hormone releasing hormones antagonists in the lung microvasculature.
Luca Marchetti and Britta Engelhardt
To maintain the homeostatic environment required for proper function of CNS neurons the endothelial cells of CNS microvessels tightly regulate the movement of ions and molecules between the blood and the CNS. The unique properties of these blood vascular endothelial cells are termed blood-brain barrier (BBB) and extend to regulating immune cell trafficking into the immune privileged CNS during health and disease. In general, extravasation of circulating immune cells is a multi-step process regulated by the sequential interaction of adhesion and signalling molecules between the endothelial cells and the immune cells. Accounting for the unique barrier properties of CNS microvessels, immune cell migration across the BBB is distinct and characterized by several adaptations. Here we describe the mechanisms that regulate immune cell trafficking across the BBB during immune surveillance and neuroinflammation, with a focus on the current state-of-the-art in vitro and in vivo imaging observations.
Chia-Pei Denise Hsu, Joshua D Hutcheson and Sharan Ramaswamy
Forces generated by blood flow are known to contribute to cardiovascular development and remodeling. These hemodynamic forces induce molecular signals that are communicated from the endothelium to various cell types. The cardiovascular system consists of the heart and the vasculature, and together they deliver nutrients throughout the body. While heart valves and blood vessels experience different environmental forces and differ in morphology as well as cell types, they both can undergo pathological remodeling and become susceptible to calcification. In addition, while the plaque morphology is similar in valvular and vascular diseases, therapeutic targets available for the latter condition are not effective in the management of heart valve calcification. Therefore, research in valvular and vascular pathologies and treatments have largely remained independent. Nonetheless, understanding the similarities and differences in development, calcific/fibrous pathologies and healthy remodeling events between the valvular and vascular systems can help us better identify future treatments for both types of tissues, particularly for heart valve pathologies which have been understudied in comparison to arterial diseases.
Alessandra Magenta, Reggio Lorde, Sunayana Begum Syed, Maurizio C Capogrossi, Annibale Puca and Paolo Madeddu
Regenerative medicine is a new therapeutic modality that aims to mend tissue damage by encouraging the reconstitution of physiological integrity. It represents an advancement over conventional therapies that allow reducing the damage but result in disease chronicization. Age-related decline in spontaneous capacity of repair, especially in organs like the heart that have very limited proliferative capacity, contributes in reducing the benefit of conventional therapy. ncRNAs are emerging as key epigenetic regulators of cardiovascular regeneration. Inhibition or replacement of miRNAs may offer reparative solutions to cardiovascular disease. The first part of this review article is devoted to illustrating novel therapies emerging from research on miRNAs. In the second part, we develop new therapeutic concepts emerging from genetics of longevity. Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.
Tumour growth critically depends on a supportive microenvironment, including the tumour vasculature. Tumour blood vessels are structurally abnormal and functionally anergic which limits drug access and immune responses in solid cancers. Thus, tumour vasculature has been considered an attractive therapeutic target for decades. However, with time, anti-angiogenic therapy has evolved from destruction to structural and functional rehabilitation as understanding of tumour vascular biology became more refined. Vessel remodelling or normalisation strategies which alleviate hypoxia are now coming of age having been shown to have profound effects on the tumour microenvironment. This includes improved tumour perfusion, release from immune suppression and lower metastasis rates. Nevertheless, clinical translation has been slow due to challenges such as the transient nature of current normalisation strategies, limited in vivo monitoring and the heterogeneity of primary and/or metastatic tumour environments, calling for more tailored approaches to vascular remodelling. Despite these setbacks, harnessing vascular plasticity provides unique opportunities for anti-cancer combination therapies in particular anti-angiogenic immunotherapy which are yet to reach their full potential.
Makeda Stephenson, Daniel H Reich and Kenneth R Boheler
The reproducible generation of human-induced pluripotent stem cell (hiPSC)-derived vascular smooth muscle cells (vSMCs) in vitro has been critical to overcoming many limitations of animal and primary cell models of vascular biology and disease. Since this initial advance, research in the field has turned toward recapitulating the naturally occurring subtype specificity found in vSMCs throughout the body, and honing functional models of vascular disease. In this review, we summarize vSMC derivation approaches, including current phenotype and developmental origin-specific methods, and applications of vSMCs in functional disease models and engineered tissues. Further, we discuss the challenges of heterogeneity in hiPSC-derived tissues and propose approaches to identify and isolate vSMC subtype populations.
Malik Bisserier, Radoslav Janostiak, Frank Lezoualc’h and Lahouaria Hadri
Pulmonary arterial hypertension (PAH) is a multifactorial cardiopulmonary disease characterized by an elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which can lead to right ventricular (RV) failure, multi-organ dysfunction, and ultimately to premature death. Despite the advances in molecular biology, the mechanisms underlying pulmonary hypertension (PH) remain unclear. Nowadays, there is no curative treatment for treating PH. Therefore, it is crucial to identify novel, specific therapeutic targets and to offer more effective treatments against the progression of PH. Increasing amounts of evidence suggest that epigenetic modification may play a critical role in the pathogenesis of PAH. In the presented paper, we provide an overview of the epigenetic mechanisms specifically, DNA methylation, histone acetylation, histone methylation, and ncRNAs. As the recent identification of new pharmacological drugs targeting these epigenetic mechanisms has opened new therapeutic avenues, we also discuss the importance of epigenetic-based therapies in the context of PH.
Piotr Kobialka and Mariona Graupera
PI3Ks belong to a family of lipid kinases that comprises eight isoforms. They phosphorylate the third position of the inositol ring present in phosphatidylinositol lipids and, in turn, activate a broad range of proteins. The PI3K pathway regulates primal cellular responses, including proliferation, migration, metabolism and vesicular traffic. These processes are fundamental for endothelial cell function during sprouting angiogenesis, the most common type of blood vessel formation. Research in animal models has revealed key functions of PI3K family members and downstream effectors in angiogenesis. In addition, perturbations in PI3K signalling have been associated with aberrant vascular growth including tumour angiogenesis and vascular malformations. Together, this highlights that endothelial cells are uniquely sensitive to fluctuations in PI3K signalling. Here, we aim to update the current view on this important signalling cue in physiological and pathological blood vessel growth.
Eleonora Zucchelli, Qasim A Majid and Gabor Foldes
Angiogenesis and vasculogenesis are complex processes by which new blood vessels are formed and expanded. They play a pivotal role not only in physiological development and growth and tissue and organ repair, but also in a range of pathological conditions, from tumour formation to chronic inflammation and atherosclerosis. Understanding the multistep cell-differentiation programmes and identifying the key molecular players of physiological angiogenesis/vasculogenesis are critical to tackle pathological mechanisms. While many questions are yet to be answered, increasingly sophisticated in vitro, in vivo and ex vivo models of angiogenesis/vasculogenesis, together with cutting-edge imaging techniques, allowed for recent major advances in the field. This review aims to summarise the three-dimensional models available to study vascular network formation and to discuss advantages and limitations of the current systems.