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• W2548642249 abstract "HomeJournal of the American Heart AssociationVol. 5, No. 11“Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop Open AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessResearch ArticlePDF/EPUB“Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop Francesca Bosetti, PharmD, PhD, Zorina S. Galis, PhD, Margaret S. Bynoe, PhD, Marc Charette, PhD, Marilyn J. Cipolla, PhD, Gregory J. del Zoppo, MD, Douglas Gould, PhD, Thomas S. Hatsukami, MD, Teresa L. Z. Jones, MD, James I. Koenig, PhD, Gerard A. Lutty, PhD, Christine Maric‐Bilkan, PhD, Troy Stevens, PhD, H. Eser Tolunay, PhD and Walter Koroshetz, MD Francesca BosettiFrancesca Bosetti National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author , Zorina S. GalisZorina S. Galis National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author , Margaret S. BynoeMargaret S. Bynoe Cornell University, Ithaca, NY Search for more papers by this author , Marc CharetteMarc Charette National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author , Marilyn J. CipollaMarilyn J. Cipolla University of Vermont, Burlington, VT Search for more papers by this author , Gregory J. del ZoppoGregory J. del Zoppo University of Washington, Seattle, WA Search for more papers by this author , Douglas GouldDouglas Gould University of California, San Francisco, CA Search for more papers by this author , Thomas S. HatsukamiThomas S. Hatsukami University of Washington, Seattle, WA Search for more papers by this author , Teresa L. Z. JonesTeresa L. Z. Jones National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author , James I. KoenigJames I. Koenig National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author , Gerard A. LuttyGerard A. Lutty Johns Hopkins University, Baltimore, MD Search for more papers by this author , Christine Maric‐BilkanChristine Maric‐Bilkan National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author , Troy StevensTroy Stevens University of South Alabama, Mobile, AL Search for more papers by this author , H. Eser TolunayH. Eser Tolunay National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author and Walter KoroshetzWalter Koroshetz National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD Search for more papers by this author and the “Small Blood Vessels: Big Health Problems” Workshop Participants‡ Originally published4 Nov 2016https://doi.org/10.1161/JAHA.116.004389Journal of the American Heart Association. 2016;5:e004389IntroductionSmall blood vessels (generally <100 μm in internal diameter) contribute to fundamental physiological processes and pathological events, but may not necessarily garner the attention associated with macrovascular physiology and disease. Major reasons for the bench‐to‐bedside research gap is the complexity and the size of small vessels throughout the body. Small vessels contain diverse cellular components and interact with a large variety of nonvascular parenchymal cell populations that differ among various organs. Depending on their location, the overlapping effect of environmental, epigenetic, and developmental factors adds to this complexity, challenging the translation of fundamental discoveries to the bedside. A better understanding of the specific structural and functional signatures of small vessels throughout the body and how their local perturbations can contribute to systemic pathophysiological conditions has the potential to transform diagnostic and therapeutic approaches.To advance this important area of science, the National Institutes of Health held a workshop on September 18–19, 2014 that brought together scientists and clinicians from diverse areas of microvascular research to share their latest discoveries, identify common challenges, and foster collaborative research on the physiology and pathology of small blood vessels in many organs and tissues. The workshop included 7 scientific sessions, entitled: (1) Basic Biology and Natural History of Small Vessels; (2) Vascular Dynamics; (3) Small Vessel Cellular Interactions; (4) Transendothelial Transport, Including Across the Blood Brain Barrier (BBB) in Health and Disease; (5) Small Vessels in Disease; (6) Effects of Internal Milieu and Disease on Small Vessels; and (7) Research Tools and Innovation. All sessions and panel discussions are available in the National Institutes of Health Videocast archive (http://videocast.nih.gov/PastEvents.asp). This white paper is not meant to be a comprehensive review of the topics. Rather it is meant to articulate the gaps and opportunities identified by the workshop participants. We regret any major omissions that might have occurred. The top scientific priorities identified by participants needing further study are summarized in Table.Table 1. Top Scientific Priorities From the National Institutes of Health (NIH) Workshop “Small Blood Vessels: Big Health Problems?”Basic biology and natural history of small vesselsUnderstand the mechanisms driving complex local specialization of endothelial cells and development of small vessels, in order to identify therapeutic targets that take into account the heterogeneity in structure and function of the endothelium between distinct organs and within a tissue and the influence of genetic determinants, sex, hormonal status, and ageVascular dynamics Visualize with spatial and temporal fidelity the critical subcellular signal transduction networks, intermolecular interactions (eg, molecular anatomy), and cell–cell and cell–matrix properties in health and diseaseSmall vessel cellular interactions Understand the molecular and cellular processes in homeostasis and response to injuries of small vessels, and how cellular and organ‐specific environments influence this responseTransendothelial transport, including blood–brain barrier, in health and disease Deconstruct the regulation and function of the neurovascular unit (including adhesion, extracellular matrix, tight and adherens junctions and transcytosis) in health, and reconstruct them in diseaseSmall vessels in disease Develop translational, mechanism‐based therapies to prevent or slow progression of small vessel diseases and define which patients to treat, and when and how to treat themEffects of internal milieu and disease on small vessels Develop better and clinically relevant models of diseases of small vessels and elucidate the interactions between vasculature, inflammation, and immune activation across the lifespanResearch tools and innovation Develop and integrate synergistic biological, technological, and computational advances in order to understand complex, dynamic interactions among different signaling pathways, cell types, cells and matrix proteins, small and large vessels, and vessels and their microenvironments, through multidisciplinary teamsBasic Biology and Natural History of Small VesselsThe common structural component of all small blood and lymphatic vessels throughout the body is the endothelium. The endothelial layer is the only common cellular component of capillaries, the simplest vascular structures with the smallest diameter. While vascular smooth muscle cells surround the endothelial layer in arterioles and venules, outside the brain pericytes are quite abundant on small venules and arterioles but are rather sparse on capillaries.1 Within the brain, however, there is controversy about pericyte coverage of capillaries.2 Heterogeneity in endothelial cells is particularly evident at the level of capillaries, where endothelial cells specifically adapt to the needs of the surrounding tissues.3 The endothelium varies in structural appearance in different organs and may be continuous, discontinuous, fenestrated, or sinusoidal in nature. Beyond controlling the highly specialized blood–tissue exchanges needed for nutrient transfer, signaling, or immune function, the endothelium performs other multiple key physiological functions, including maintaining antithrombotic surface and in arterioles the vasomotor tone.4 In fact, the endothelium can be viewed as one organ, a giant mosaic whose parts follow patterns that are shaped by environmental and developmental factors.5, 6Much remains to be learned about the mechanisms involved in vascular development, including the bridge that connects vascular development with endothelium specialization; the molecular and physical factors that determine the precise temporal arrangement, shape, branching, and size of the vasculature; and the elements that modulate endothelial barrier function (Figure 1).7 This session identified the need for interdisciplinary teams to help decode the entire normal and pathological tissue‐specific molecular heterogeneity patterns of the endothelium. This knowledge is needed to develop better prognostic and diagnostic markers for a variety of local and systemic diseases, and might one day allow the precise tissue targeting of new therapies by delivery to the correct “endothelial ZIP‐code.”8Download PowerPointFigure 1. Differences in the functional small blood vessel architecture and normal perfusion of various mouse organs. Systemically injected fluorescent microspheres are tightly contained with the vascular structures with continuous endothelium, exemplified in skeletal muscle and brain by the smooth appearance of the small vessels. In contrast, microspheres cross through the fenestrated endothelium of kidney glomeruli and escape through the pores of the discontinuous endothelium of spleen sinusoids (Zorina Galis, unpublished data).The function of the endothelial lining involves significant “cross‐talk” within the vessel wall, between the endothelial and mural vascular cells, and between bloodborne cells and signals, small vessels, and their surrounding tissues. Integration of the vascular structure and function across spatial and temporal scales, from genes to tissue, is key to understanding vascular development and physiological and pathological remodeling. Angiogenesis, arteriogenesis, the growth of collateral vessels, and the regression of vascular structures are dynamic events that can occur over a relatively short time span. These remodeling phenomena may affect an individual's propensity to adverse events such as myocardial infarction and stroke, and their manifest severity, and are influenced by individual genetic and environmental factors.9, 10 Different strains of mice exhibit differences in arteriogenesis, depending on the location of preexisting connections between arterioles, as well as differences in their susceptibility to disease,11 supporting the role of genetics in vascular remodeling. For instance, the density of brain collateral circulation is strongly determined by genetic background and is an important determinant of stroke outcome in animals and potentially humans.12, 13Similarly, facets of the lymphatic system that can influence inflammation and the vascular response to disease are also genetically determined.14 It is less clear, however, what particular genes specify variation in the formation, maintenance, and remodeling of small vessels. Furthermore, there is a paucity of information about how genetic variants influence the response of small vessels across the lifespan. Some genetic susceptibility factors seem to be shared across different manifestations of small vessel disease.15Recent data indicate that pericytes can control microvascular remodeling and angiogenic switching.16 “Angiophagy,” leading to the loss of vascular structures (also recognized in aging), also emerged as potentially critical for vascular occlusion and recanalization.17, 18, 19 It is recognized by this session that new computational approaches that could integrate all factors that affect vascular development and remodeling to simulate these processes using stochastic or deterministic rules could greatly advance the ability to predict individual risk and possibly prevent disease.Sex is a critical biological determinant that modulates microvascular pathophysiology.20 The relative concentration of sex hormones that exist both in males and females varies, which means the sex biological biasing factors vary across the lifespan.21 Sex differences occur in incidence and presentation of cardiovascular disease, chronic kidney disease, and vascular dementia.22, 23, 24 Preeclampsia, menopause, and erectile dysfunction are sex‐specific conditions reflexing the complement of sex chromosomes and sex hormones,25 and are associated with small blood vessel dysfunction, but we still do not understand these associations at a fundamental level. Hormonal variation affects expression of genes, and mosaicism of X inactivation in females may not be as random as previously thought. Interestingly, changes in small vessel structure (such as remodeling) and function can be markedly different in males and females, or in response to sex hormones. For example, fluctuating levels of sex hormones have important consequences on stroke outcome in female animals, and marked changes in the endothelial lining of small blood vessels appear during pathologies associated with pregnancy such as preeclampsia and eclampsia.26, 27, 28, 29, 30 In the peripheral microcirculation, endothelin‐mediated vasoconstriction or nitric oxide–mediated endothelium‐dependent vasodilation is significantly affected by sex steroids and may underlie pathology in polycystic ovary syndrome.31 Therefore, careful attention should be given to sex and reproductive history in experimental design for both preclinical and clinical research. An integrative approach is needed to discover how sex affects vascular function within all components of the circulatory system.To advance the understanding of small vessel disease, cross‐disciplinary research and the development of new tools that include computational modeling and imaging could enable integration of data across scales, ranging from molecular to tissue levels. Additionally, the field needs to better understand the mechanisms driving complex local structural and functional specialization of endothelial cells and how blood vessels develop and remodel across the lifespan. A better definition of “small vessel disease” that can affect the brain, heart, kidney, or other organs, as well as an integrative approach to discerning causation of small vessel disease are needed to identify new diagnostics and therapeutic targets and biomarkers.Vascular DynamicsThe vascular tone (resistance) is regulated to match blood flow to metabolic demand in order to provide adequate profusion to tissues under different physiological conditions. As an example, afferent and efferent arteriole resistances are differentially controlled to regulate filtration dynamics in the glomerular capillaries that lie in between these portal resistance elements. Mechanical forces are stimuli that mediate these regulatory effects. Mechanosensation of blood pressure and flow contributes to vasculogenesis and vascular remodeling. Alterations in transduction of the mechanical signal, ie, mechanotransduction, are associated with disease processes such as hypertension, diabetes, atherosclerosis, and large vessel stiffening. Although many putative mechanotransducers have been identified,32 much work remains to be done to understand in detail how these various components orchestrate responses to shear stress.Many challenges remain for understanding vascular dynamics. At the macro‐scale, it is important to identify specific sensors in endothelial and vascular smooth muscle cells, their biochemical and cellular signaling pathways in different organs, and their synergy with systemic risk factors in disease progression. At the meso‐scale, work is needed to characterize microvascular cellular topology in relationship to organ function. At the micro‐scale, it is important to elucidate how single cell function within small blood vessels themselves influences the vasculature. These goals can be achieved through a better understanding of microanatomy and microphysiology, genomics, proteomics, and metabolomics throughout the circulatory system. Opportunities for scientific advances include elucidating the heterogeneity of cellular phenotypes; understanding the mechanics and development of the matrix, and the long‐range interactions (mechanical, electrochemical, and bloodborne); developing cell‐free scaffolds to be used for tissue engineering; imaging in 3 dimensions with high temporal and spatial resolution; and mathematical modeling to integrate these concepts with real vascular dimensions, functions, and biochemical processes.Several gaps remain in our understanding of the role of the microcirculation in important fundamental mechanisms in health and in disease, such as metabolic hyperemia and the etiology of small vessel disease (SVD). For example, much remains to be understood regarding the causal relationship between coronary microvascular disease and ischemic heart disease. New methods for high‐resolution ex vivo imaging and morphometry of the entire coronary vasculature in pigs, other large mammals,33and mice34 will help fill these gaps. However, technological advances, such as biosensors for understanding intracellular and macro‐scale signaling and mechanics; higher resolution and speed, imaging technologies that can penetrate into deeper layers of tissues in vivo, including intrinsic fluorescence; fate mapping for disease etiology, eg, site for angiogenesis; and new transgenic and conditional animal models are needed to further advance the field.Small Blood Vessel Cellular InteractionsAlthough the microvasculature shares common structural and functional characteristics in many organs, there are also important organ‐specific features. Endothelial cells of small vessels closely interact with smooth muscle cells, pericytes, and tissue‐specific nonvascular cells, as well as circulating or tissue resident immune cells. Vascular smooth muscle cells interact and communicate with endothelial cells in the control of vascular tone. Nonvascular and vascular interactions shape the physiological responses and pathophysiological outcomes following injury and in microvascular complications.7 These interactions are in turn influenced by microenvironment and organ‐specific drivers.35 For instance, antibody‐mediated inflammation and injury of glomerular capillaries, which carry out the first step of filtering blood, underlie many glomerular disorders in the kidney.36The immune system changes with aging toward a more aggressively pro‐inflammatory state. Alterations in the adaptive and innate immune system contribute to age‐associated morbidity and mortality, and increased pro‐inflammatory cytokines (eg, interleukin‐6, tumor necrosis factor‐α) in aging have been associated with hypertension, atherosclerosis, dementia, and diabetes, among other diseases. However, there is a strict territorial behavior of inflammatory disease, and aging is not always the cause. Elucidating the role of inflammation on vascular health and disease constitutes an important scientific gap.Many features of the immune interactions with small blood vessels remain poorly understood. These immune interactions include target organ susceptibility factors that dictate the extent of the immune response and damage initiated by deposited antibodies37; differences in the characteristics of immune responses following deposition of soluble immune complex versus in situ immune complex formation; and the mechanisms by which neutrophils and their cross‐talk with other immune cells induce injury. For example, in the kidney, work is needed to understand how immune cells contribute to chronic glomerulonephritis; how glomerular inflammation leads to tubulo‐interstitial damage, which predicts the progression to end‐stage renal disease; and, how microvascular inflammation increases the risk for macrovascular disease (eg, atherosclerosis). Some similarities between the pathology of small blood vessel disease in the kidney and the brain suggest that similar mechanisms may be at work.Excessive oxidative stress of cells of the vascular wall resulting from altered metabolism, inflammatory cytokines, or mechanical forces contributes to vascular diseases. However, large clinical trials in which antioxidants have been given in high‐risk patients for the prevention of cardiovascular events did not demonstrate the expected benefits,38, 39, 40 in part because redox‐responsive pathways that induce specific organ pathology have remained elusive. Obstacles to deciphering specific redox‐dependent pathways are the localized nature of reactive oxygen species (ROS) production (eg, in caveolae, lipid rafts, endosomes, or mitochondria), the particular properties of the oxidants (eg, superoxide, peroxynitrite), and the plethora of chemical protein modifications (eg, sulfenylation, glutathionylation) and their reversible nature.41 New technologies to resolve intracellular reactive oxygen species spatially and temporally, integrated in silico algorithms to predict redox modifications, and reliable methods to identify redox modifications by mass spectroscopy would facilitate progress in understanding vascular oxidative stress. Additionally, redox signaling occurs in parallel to other key signaling events, eg, calcium‐ and reactive oxygen species–dependent signaling pathways, which can interact and modulate the activity of each other.42 An integrated approach is required to determine the physiological relevance of specific vascular redox pathways and their interplay with other key processes in the adjacent cells and within tissues.Ex vivo vascular modeling systems could provide the opportunity to study disease mechanisms. Such systems have been used to investigate thrombosis, in particular, self‐assembly of von Willebrand factor, endothelial barrier function, angiogenesis, and diseases affecting small vessels including thrombotic microangiopathies (including thrombotic thrombocytopenic purpura), sepsis, malaria, and sickle cell disease.43 These systems allow the effect of changes in different physiological or pathological parameters, such as shear stress, flow rates, vessel geometry, and role of other cell types to be studied in real‐time. However, the systems need to be improved to overcome low throughput and developed to apply to the central nervous system (CNS) and other organs.Transendothelial Transport, Including Across the BBB, in Health and DiseaseThe major microvascular barriers of the brain, the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier, and of peripheral nerves, the blood–nerve barrier (BNB), share unique properties required to tightly regulate the transport of ions, solutes, nutrients, and macromolecules between the peripheral circulation and the neural parenchyma, as well as control hematogenous leukocyte trafficking during physiologic and pathophysiologic conditions. The BBB is a very restrictive layer of highly specialized endothelial cells that exist throughout the brain vessels, and is even more specialized in capillaries and the inner layers of postcapillary venules in the brain (Figure 2A). In the brain, processes from neighboring astrocytes and microglial cells contribute to the BBB, forming the neurovascular unit (Figure 2B). These cells can regulate barrier function, contributing to the internal homeostasis of the brain as required for signal transduction. Blood cells, particularly polymorphonuclear cells, lymphocytes, and monocytes, also interact with the endothelium and may affect the neurovascular unit.44 Similarly, the BNB is formed by specialized endothelial cells that form microvessels within the innermost layer of peripheral nerves and nerve roots (the endoneurium).45 These endothelial cells exhibit highly restricted pinocytosis and transcytosis potential, express specific transporters that regulate the influx/efflux of nutritive/toxic compounds, express low levels of leukocyte adhesion molecules under normal physiologic states and an array of specialized proteins that form tight and adherens intercellular junctions that efficiently restrict passive diffusion of bloodborne molecules and contribute to a high transendothelial electrical resistance (Figure 3A). In addition, extracellular matrix adhesion of endothelial cells by integrins can determine tight junction fidelity.46 These specialized endothelial cells are surrounded by pericytes that share a common basement membrane.Download PowerPointFigure 2. A, The neurovascular unit at the level of a pial arteriole (Courtesy of Dr Giuseppe Faraco, Weill Cornell Medical College). B, Perivascular microglial cells. This deconvolution fluorescence microscopy image illustrates the proximity of microglial cells to a cerebral capillary in the adult rat hindbrain. A 30‐μm frozen rat brain section was stained for Iba1 (red), a microglial marker, and MHC II (green), which is upregulated in activated microglia but also stains endothelial cells. Nuclei were stained with 4′,6‐diamidino‐2‐phenylindole (DAPI) (blue). Microglia are the resident macrophage of the CNS and serve a number of roles including defense against pathogens that cross the BBB. Note the difference between the “surveillance state” microglia (white arrow), which has a small amount of punctate green MHCII staining on the processes and the “activated” microglia (yellow arrow), which has increased punctate MHCII staining that defines the outline of the processes. The capillary, indicated by the green MHCII staining, winds between the 2 microglial cells. This image is a maximum intensity projection of a 10‐μm‐thick segment of the brain slice. BBB indicates blood–brain barrier; CNS, central nervous system; EC, endothelial cell; PVM, perivascular macrophage; SMC, smooth muscle cell.Download PowerPointFigure 3. A, Tight junctions at the human blood–nerve barrier (BNB). A digital electron micrograph of the BNB in the sural nerve from an untreated adult patient with Guillain‐Barré syndrome shows intact electron‐dense intercellular tight junctions (white arrows). Scale bar=0.5 μm. B, Human BNB alterations in disease. A digital electron micrograph of the BNB in the sural nerve from an adult patient with chronic inflammatory demyelinating polyneuropathy shows BM thickening/duplication between endoneurial EC and pericytes (P). Intact electron‐dense intercellular tight junctions (white arrows) are seen. Perivascular T‐lymphocytes (TL), a common feature in immune‐mediated polyneuropathies, are also observed. Scale bar=5 μm. BM indicates basement membrane; EC, endothelial cell; L, lumen; P, pericyte; RBC, red blood cell.Altered BBB permeability has been implicated in small vessel disease, lacunar stroke, vascular dementia, and Alzheimer's disease.47 Alternations in BNB structure, such as basement membrane thickening (Figure 3B), have been described in chronic peripheral nerve disorders such as diabetic neuropathy and chronic inflammatory demyelinating polyneuropathy.48A special paravascular space described in the rodent brain serves as a lymphatic system in the CNS.49 This highly polarized macroscopic fluid transport system has been termed the “glymphatic” system. Aging and microinfarcts appear to be linked to a marked reduction in glymphatic activity. Alzheimer's disease is also thought to be a consequence of altered perivascular drainage due to faulty removal of β‐amyloid from the brain by the glymphatic transport and accumulation of β‐amyloid proteins. The effects of changes in BBB permeability, hypertension, diabetes, SVD, and other comorbidities on glymphatic clearance, as well as the role of individual cell types in the neurovascular unit on glymphatic activity, are unknown. More importantly, the presence of the glymphatic system in the human brain remains to be demonstrated, which requires development of human biomarkers of glymphatic activity.Cerebral SVD can be sporadic or hereditary, and is characterized by leakage of plasma proteins into the vessel walls and perivascular spaces. SVD is thought to play a role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, dementia, and cognitive decline, retinal vasculopathy with cerebral leukodystrophy, white matter disease, and lacunes of the central gray matter. The processes initiating SVD of the CNS are not exactly known but may involve hypoxia/ischemia, inflammation, pericyte degeneration, and alteration in BBB capillary function, resulting in BBB leakage. Improvements in neuroimaging and studies in animal models are needed to address gaps in knowledge of the etiology, risk factors, or triggers of SVD.Transcellular transport is another dynamic process that needs to be further elucidated. Depending on the tissue or the disease state, the passage of a macromolecule from peripheral circulation into the CNS or peripheral nerves could be the result of increased paracellular entry attributable to alterations in intercellular tight junction function or an active transport process (eg, receptor‐ or caveolae‐mediated transcytosis). Advancing knowledge of the repertoire of transporters and their function, expression," @default.
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• W2548642249 title "“Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop" @default.
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