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JAMA Neurology Oct 2018Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although... (Review)
Review
IMPORTANCE
Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow.
OBSERVATIONS
When the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis. Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD). During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS.
CONCLUSIONS AND RELEVANCE
Questions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process. The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use. Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored. Recent advances in mapping the brain vasculome may generate new hypotheses. The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms.
Topics: Humans; Stroke, Lacunar
PubMed: 30167649
DOI: 10.1001/jamaneurol.2018.1073 -
Cell Metabolism Sep 2021Wound healing requires cooperation between different cell types, among which macrophages play a central role. In particular, inflammatory macrophages are engaged in the... (Review)
Review
Wound healing requires cooperation between different cell types, among which macrophages play a central role. In particular, inflammatory macrophages are engaged in the initial response to wounding, and alternatively activated macrophages are essential for wound closure and the resolution of tissue repair. The links between temporal activation-induced changes in the metabolism of such macrophages and the influence this has on their functional states, along with the realization that metabolites play both intrinsic and extrinsic roles in the cells that produce them, has focused attention on the metabolism of wound healing. Here, we discuss macrophage metabolism during distinct stages of normal healing and its related pathologic processes, such as during cancer and fibrosis. Further, we frame these insights in a broader context of the current understanding of macrophage metabolic reprogramming linked to cellular activation and function. Finally, we discuss parallels between the metabolism of macrophages and fibroblasts, the latter being a key stromal cell type in wound healing, and consider the importance of the metabolic interplay between different cell types in the wound microenvironment.
Topics: Fibroblasts; Fibrosis; Humans; Macrophages; Wound Healing
PubMed: 34384520
DOI: 10.1016/j.cmet.2021.07.017 -
International Review of Cell and... 2012Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent... (Review)
Review
Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.
Topics: Animals; Cell Biology; Cell Death; Fetus; Humans; Models, Biological; Reperfusion Injury; Risk Factors
PubMed: 22878108
DOI: 10.1016/B978-0-12-394309-5.00006-7 -
Blood Jul 2015Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating... (Review)
Review
Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet's origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet's involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.
Topics: Animals; Anticarcinogenic Agents; Aspirin; Blood Platelets; Cell Death; Cell Proliferation; Cell-Derived Microparticles; Humans; Inflammation; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Neovascularization, Pathologic; Neutrophils; Signal Transduction; Thrombosis; Tumor Escape
PubMed: 26109205
DOI: 10.1182/blood-2014-08-531582 -
Blood Jul 2018Several important physiological processes, from permeability to inflammation to hemostasis, take place at the vessel wall and are regulated by endothelial cells (ECs).... (Review)
Review
Several important physiological processes, from permeability to inflammation to hemostasis, take place at the vessel wall and are regulated by endothelial cells (ECs). Thus, proteins that have been identified as regulators of one process are increasingly found to be involved in other vascular functions. Such is the case for von Willebrand factor (VWF), a large glycoprotein best known for its critical role in hemostasis. In vitro and in vivo studies have shown that lack of VWF causes enhanced vascularization, both constitutively and following ischemia. This evidence is supported by studies on blood outgrowth EC (BOEC) from patients with lack of VWF synthesis (type 3 von Willebrand disease [VWD]). The molecular pathways are likely to involve VWF binding partners, such as integrin αvβ3, and components of Weibel-Palade bodies, such as angiopoietin-2 and galectin-3, whose storage is regulated by VWF; these converge on the master regulator of angiogenesis and endothelial homeostasis, vascular endothelial growth factor signaling. Recent studies suggest that the roles of VWF may be tissue specific. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal bleeding resulting from vascular malformations. In this article, we review the evidence showing that VWF is involved in blood vessel formation, discuss the role of VWF high-molecular-weight multimers in regulating angiogenesis, and review the value of studies on BOEC in developing a precision medicine approach to validate novel treatments for angiodysplasia in congenital VWD and acquired von Willebrand syndrome.
Topics: Angiodysplasia; Animals; Biomarkers; Blood Vessels; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Signal Transduction; von Willebrand Diseases; von Willebrand Factor
PubMed: 29866817
DOI: 10.1182/blood-2018-01-769018 -
Interventional Cardiology Clinics Jul 2016Contemporary endovascular stents are the product of an iterative design and development process that leverages evolving concepts in vascular biology and engineering.... (Review)
Review
Contemporary endovascular stents are the product of an iterative design and development process that leverages evolving concepts in vascular biology and engineering. This article reviews how insights into vascular pathophysiology, materials science, and design mechanics drive stent design and explain modes of stent failure. Current knowledge of pathologic processes is providing a more complete picture of the factors mediating stent failure. Further evolution of endovascular stents includes bioresorbable platforms tailored to treat plaques acutely and to then disappear after lesion pacification. Ongoing refinement of stent technology will continue to require insights from pathology to understand adverse events, refine clinical protocols, and drive innovation.
Topics: Absorbable Implants; Coronary Restenosis; Drug-Eluting Stents; Endovascular Procedures; Humans; Prosthesis Design; Prosthesis Failure; Stents
PubMed: 28582036
DOI: 10.1016/j.iccl.2016.02.006 -
Journal of the American Heart... Jun 2023Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. Biomarkers, molecules measurable in the... (Review)
Review
Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. Biomarkers, molecules measurable in the blood, could inform the clinician by aiding in the diagnosis and management of coronary microvascular dysfunction. We present an updated review of circulating biomarkers in coronary microvascular dysfunction representing key pathologic processes, including inflammation, endothelial dysfunction, oxidative stress, coagulation, and other mechanisms.
Topics: Humans; Coronary Artery Disease; Biomarkers; Myocardial Ischemia; Inflammation; Oxidative Stress; Coronary Vessels
PubMed: 37301749
DOI: 10.1161/JAHA.122.029341 -
Journal of Cellular and Molecular... May 2020Much of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and... (Review)
Review
Much of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and ligament (HOTL). Unmet need and no effective treatment has been developed for HOTL, primarily attributable to poor understanding of cellular and molecular mechanisms. HOTL forms via endochondral ossification, a common process of most kinds of HO. HOTL is a dynamic pathologic process that includes trauma/injury, inflammation, mesenchymal stromal cell (MSC) recruitment, chondrogenic differentiation and, finally, ossification. A variety of signal pathways involve HOTL with multiple roles in different stages of HO formation, and here in this review, we summarize the progress and provide an up-to-date understanding of HOTL.
Topics: Biomarkers; Disease Susceptibility; Ligaments; Mesenchymal Stem Cells; Ossification, Heterotopic; Signal Transduction; Tendons
PubMed: 32293797
DOI: 10.1111/jcmm.15240 -
Journal of Vascular Surgery. Venous and... Jul 2017Our understanding of the pathophysiologic process of venous ulceration has dramatically increased during the past two decades because of dedicated, venous-specific basic... (Review)
Review
Our understanding of the pathophysiologic process of venous ulceration has dramatically increased during the past two decades because of dedicated, venous-specific basic science research. Currently, the mechanisms regulating venous ulceration are a combination of macroscopic and microscopic pathologic processes. Macroscopic alterations refer to pathologic processes related to varicose vein formation, vein wall architecture, and cellular abnormalities that impair venous function. These processes are primarily caused by genetic factors that lead to the destruction of normal vein wall architecture and venous hypertension. Venous hypertension causes a chronic inflammatory response that over time can cause venous ulceration. The inciting inflammatory injury is chronic extravasation of macromolecules and red blood cell degradation products and iron overload. Chronic inflammation causes white blood cell extravasation into the dermis with secretion of numerous proinflammatory cytokines. These cytokines transform the phenotype of fibroblasts to a contractile phenotype that increases tension in the dermis. In addition, iron overload keeps macrophages in an M1 phenotype, which leads to tissue destruction instead of dermal repair. Current surgical and medical therapies are primarily directed at eliminating venous hypertension and promoting venous ulcer wound healing. Despite advances in our understanding of venous ulcer formation and healing, ulcers still take an average of 6 months to heal, and ulcer recurrence rates at 5 years are >58%. To improve the care of patients with venous ulcers, we need to further our understanding of the underlying pathologic events that lead to ulcer formation, prevent healing, and decrease ulcer-free recurrence intervals.
Topics: Chronic Disease; Cytokines; Humans; Inflammation; Leukocytes; Recurrence; Varicose Ulcer
PubMed: 28624002
DOI: 10.1016/j.jvsv.2017.03.015 -
Romanian Journal of Morphology and... 2017In the vascular system, angiogenesis and arteriogenesis play a unique yet equally important role in both health and disease. Angiogenesis, the formation of new blood... (Review)
Review
In the vascular system, angiogenesis and arteriogenesis play a unique yet equally important role in both health and disease. Angiogenesis, the formation of new blood vessels from a preexisting vascular bed, occurs naturally during wound healing, the female menstrual cycle and pregnancy. It plays a critical role in tissue growth and repair, and is a highly controlled process that is dependent on an intricate balance of both pro-angiogenic (to stimulate) and anti-angiogenic (to negatively regulate the phenomenon) factors. Otherwise, the term arteriogenesis refers to anatomic transformation of preexisting arterioles with increasing lumen area and wall thickness, due to a thick muscular layer and purchasing of visco-elastic and vasomotor capacities. Arteriogenesis differs from angiogenesis in several aspects, the most important being the dependence of angiogenesis on hypoxia and the dependence of arteriogenesis on inflammation. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis.
Topics: Cell Hypoxia; Female; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A
PubMed: 28523292
DOI: No ID Found