The diseases of the small vessels are the starting point for major diseases such as high blood pressure, diabetes, strokes, heart attacks, dementia and other brain-related diseases …
“Small Blood Vessels: Big Health Problems?”: Scientific Recommendations of the National Institutes of Health Workshop
Francesca Bosetti et al. American Heart Association* (published on November 4, 2016)
2016 Nov 4;5(11):e004389. – doi: 10.1161/JAHA.116.004389.
Introduction
Small 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.
| Basic biology and natural history of small vessels | Understand 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 age |
| Vascular 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 disease |
| Small 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 response |
| Transendothelial 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 disease |
| Small 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 them |
| Effects 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 lifespan |
| Research 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 teams |
Basic Biology and Natural History of Small Vessels
The 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, 6
Much 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.”8
Figure 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).
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Core source: https://pubmed.ncbi.nlm.nih.gov/27815267/
Original source, Journal of the American Heart Association : https://www.ahajournals.org/doi/10.1161/JAHA.116.004389
