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Vascular Biology
Cristina Sanina1, Olga L. Bockeria2, Karlo A. Wiley3 and Jonathan E. Feig4
1Department of Internal Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
2Department of Cardiovascular Surgery, Bakoulev Center for Cardiovascular Surgery, Moscow, Russia
3Cornell University, College of Agriculture and Life Sciences, Ithaca, NY, USA
4Johns Hopkins Heart and Vascular Institute, The Johns Hopkins Hospital, Baltimore, MD, USA
Introduction
Like many contemporary sciences, vascular biology has been progressively developing at the junction of many disciplines. New knowledge has been obtained in regard to vessel growth biology, physiology, and genetics as well as physiological and pathophysiological mechanisms underlying endothelial dysfunction and atherogenesis. Based on studies that extend back to the 1920s, regression and stabilization of atherosclerosis in humans have gone from just a dream to something that is achievable. Review of the literature indicates that successful attempts at regression applied robust measures to improve plasma lipoprotein profiles. Examples include extensive lowering of plasma concentrations of atherogenic apolipoprotein B and enhancement of reverse cholesterol transport from atheromata to the liver. Possible mechanisms responsible for lesion shrinkage include decreased retention of atherogenic apolipoprotein B within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of lesional foam cells out of the arterial wall, and an influx of healthy phagocytes that remove necrotic debris as well as other components of the plaque. Until very recently, with the approval of the PCSK9 inhibitors, the available clinical agents caused less dramatic changes in plasma lipoprotein levels, and thereby failed to stop most cardiovascular events. In addition, although the use of angioplasty and stenting has undoubtedly been beneficial, it does not offer a cure or address the underlying mechanisms of vascular disease.
Vascular Anatomy
Blood vessels are composed of three layers: the inner lining of intima (a monolayer of endothelial cells), the middle layer, the media (a layer or layers of vascular smooth muscle cells), and the outer layer, the adventitia (contains collagen type 1, elastic fibers, myofibroblasts, mesenchymal stem cells, vasa vasorum, and nerves). These three layers are separated with internal and external elastic laminas, a thin layer of connective tissue. Large arteries contain more layers of smooth muscle cells and more elastin, and mediumâsized arteries contain more collagen. The smallest vessels (capillaries) are built from a single layer of endothelial cells with surrounding basal lamina and pericytes. A number of pericytes and their functions differ in respect to the organs in which they are found. Vascular smooth muscle cells and pericytes regulate peripheral vascular resistance, vascular diameter, and direction of blood flow [1].
Endothelium, the Largest Body Organ
The endothelium is a large and complex organ with endocrine, autocrine, and paracrine proprieties that produces nitric oxide (NO), endothelinâ1, prostacyclinâ2, interleukinâ6, vascular endothelial growth factor (VEGF), von Willebrand factor, plasminogen activator, plasminogen activator inhibitorâ1, angiopoietinâ2, adhesion molecules such as Pâselectin, Eâselectin, integrins, and other bioactive molecules. Endothelium controls the recruitment of inflammatory cells and thrombocytes, regulates the coagulation process, extravasation, and vascular tone, and is involved in wound healing through angiogenesis. Endothelial cells cover the entire vasculature in vertebrates with the largest estimated surface amounting to 3000â6000 m2. The total weight of endothelium in an adult person is approximately 720 g, of which 600 g is capillaries [2]. Interestingly, endothelial cells not only from arteries and veins but also from different tissues possess diverse tissueâspecific protein expression [3]. NO is a major vasodilator molecule that was discovered by Dr. Furchott in 1980 and named endotheliumâderived relaxing factor. In 1992 NO was identified and in 1998 three US scientists, Robert F. Furchott, Louis J. Ignarro, and Ferid Murad, were awarded the Nobel Prize for NO discovery [4]. NO plays an essential role in vascular smooth muscle cell relaxation, thrombocyte aggregation, endothelial cell turnover, and immune/antiâinflammatory processes. Endogenous NO is generated from Lâarginine by a family of three calmodulinâdependent NO synthase (NOS) enzymes that are primarily expressed by three cell types: endothelial cells (eNOS), neurons (nNOS), and immune cells (iNOS) [5]. However, NO can also be released nonâenzymatically from Sânitrosothiols or nitrate/nitrate. Decreased production or bioavailability of NO and increased expression of endothelinâ1, an endotheliumâderived potent vasoconstrictor, suggest endothelial dysfunction and are associated with hypertension, inflammation, prothrombogenesis, atherogenesis, and cardiovascular events [1]. Inflammation or an increase in proinflammatory circulating molecules such as interleukinâ1 and interleukinâ6, tumor necrosis factorâα, Câreactive protein, and neutrophils and macrophages boost Câreactive protein production by the liver which, in turn, causes eNOS downregulation and increases endothelinâ1 bioavailability, leading to decreased vasodilation, increased shear stress, and vascular atherogenesis. In particular, inflammation upregulates the expression of endothelial cell adhesion molecules that facilitate lowâdensity lipids (LDLs) and macrophage migration across the vascular endothelium via monocyte chemoattractant protein 1 [6]. Inflammatory cytokines also induce tissue factor and von Willebrand factor synthesis by endothelial cells, initiating coagulation cascade and platelet aggregation. Metalloproteinase ADAMTSâ13, also produced by endothelial cells, stellar liver cells, platelets, and kidney podocytes, cleaves large molecules of von Willebrand factor, but inflammatory conditions decrease ADAMTSâ13 activity, promoting the prothrombotic state. Endothelial cells also provide a rescue mechanism for thrombogenesis by continually producing tissue plasminogen activator, which is cleared by the liver unless fibrin binds to it. Furthermore, inflammatory cytokines promote endothelial cells to produce another tissue plasminogen activatorâurokinaseâtype to cleave substantial fibrin deposition. Thrombin, a procoagulation protease that converts soluble fibrinogen into insoluble fibrin, in turn activates eNOS leading to NO and prostacyclinâ2 production, causing vasodilatation and platelet aggregation inhibition. In this way endothelium regulates thrombogenesis and thrombolysis [2].
Vasculogenesis, Angiogenesis, and Arteriogenesis
Endothelial cells originate from mesoderm (hemangioblasts), which gives rise to hematopoietic stem cells and endothelial progenitor cells (angioblasts). The vascular network is formed due to three primary processes: vasculogenesis, angiogenesis, and arteriogenesis. The term âvasculogenesisâ was defined by Risau in 1997 as the de novo formation of vessels from endothelial progenitor cells, i.e. angioblasts [7]. During vasculogenesis stem cells form primitive primary vascular plexus, i.e. capillaries. Initially, it was considered ...
