The media, usually the thickest layer of the arterial wall, is responsible for the mechanical properties of the vessel Its structural components are vascular smooth muscle cells and extracellular matrix, the latter consisting of elastic lamellae, collagen fibers, structural glycoproteins, and ground substance.1 Vascular smooth muscle cells maintain vascular tone through contraction and relaxation, while the extracellular matrix of the media provides a structural framework for optimal functioning of the blood vessels The elastic fibers in the media, arranged in concentric lamellae that form the boundaries between layers of vascular smooth muscle cells, are 90% composed of elastin Cross-linking of elastin confers elasticity to the arteries In addition, elastin has been implicated in the control of proliferation and phenotype of smooth muscle cells.2 Elastin has an estimated half-life of more than 40 years in humans; its rate of synthesis is thought to be negligible in adulthood.3–5 Elastin, damaged by degenerative and pathologic processes, is unlikely to be replaced Other constituents of elastic fibers include microfibrillar-associated glycoproteins and fibrillin.6–8 Fibrillin forms a microfibrillar network that serves as scaffolding for the deposition of elastin and assembly of elastic fibers Fibulin-5, through its interactions with elastin and integrins, plays a critical role during elastic fiber development9,10 and is a potential therapeutic agent for the treatment of elastinopathies.11 Other structural glycoproteins in the arterial wall include fibronectin, vitronectin, laminin, entactin/nidogen, tenascin, and thrombospondin.12,13 Collagens are composed of three polypeptide α chains arranged to form a triple helix, which confers tensile strength to the vessel wall Types I and III collagen are the major fibrillar collagens in blood vessels, constituting about 90% of vascular collagens.14 Collagen is the stiffest component of the arterial wall, with an elastic modulus of 108 to 109 dyne/cm2.15 By contrast, the elastic modulus of elastin is in the order of 106 dyne/cm2.16,17 Hence the absolute and relative quantities of elastin and collagen contribute significantly to the stiffness of the arterial wall Elasticity of the arterial wall is a nonlinear function of transmural pressure Proposed models of this nonlinear function take into account the contribution of vascular smooth muscle cells, viscoelastic properties of the matrix proteins, residual stresses due to growth and remodeling, and gradual recruitment of collagen fibers with increasing pressure.18–21 The ground substance is filled by proteoglycans Proteoglycans are macromolecules that possess one or more linear glycosaminoglycan chains linked to a core protein The proteoglycans in the vessel wall are hyaluronan, versican, biglycan, decorin, lumican, syndecans, fibroglycan, and glypican.22 The proteoglycans have diverse roles in the organization of connective tissue structure, regulating cellular activities and metabolism, permeability, filtration, and hydration, and controlling cytokine bioavailability and stability.23–26 Matrix metalloproteinases play a fundamental role in the degradation of vascular extracellular matrix27 during physiologic and pathologic vascular remodeling.22,28 The distribution of structural components within the media varies along the arterial tree.29 With increasing distance from the heart, the elastin-to-collagen ratio falls and smooth muscle cells increase.30,31 Alterations of structural components of the media as a result of degeneration, genetic mutations, or imbalance between the synthesis and degradation of extracellular matrix have a significant impact on the mechanical properties of the vessels The adventitia contains mainly fibroblasts and collagen fibers and some elastic fibers It contributes also to the elastic properties of arteries.32,33 Nutrient vessels, vasa vasorum, arise from a branch of the artery or from a neighboring vessel to ramify and distribute to the adventitial layer Endothelial Function The endothelium comprises a monolayer of endothelial cells lining the vascular lumen It is strategically located between circulating blood components and vascular smooth muscle cells to exert a pivotal role in vascular homeostasis By producing a wide variety of substances, the endothelium regulates vascular tone, inhibits smooth muscle cell proliferation and migration, controls cellular adhesion, regulates inflammation, and exerts fibrinolytic and antithrombotic actions The concept of endothelial function is also extended from the vascular lumen to the vascular wall and adventitia, which are supplied by vasa vasorum, considered to be an active intravascular microcirculation.34,35 Nitric oxide, initially identified as the endothelium-derived relaxing factor,36 is the major vasodilating substance released by the endothelium Nitric oxide is synthesized from L-arginine by the action of endothelial nitric oxide synthase, primarily in response to shear stress produced by blood flow.37 Cofactors including tetrahydrobiopterin and nicotinamide adenine dinucleotide phosphate are involved in nitric oxide production.38 Apart from shear stress, endothelial nitric oxide synthase is also activated by bradykinin, adenosine, vascular endothelial growth factor, and serotonin.39 Asymmetric dimethylarginine, on the other hand, is an endogenous inhibitor of nitric oxide synthase40 and may mediate the adverse effects of traditional risk factors on endothelial vasodilator function.41 Nitric oxide has a half-life of a few seconds in vivo It diffuses from endothelial cells to exert its relaxation effects on vascular smooth muscle cells by activating guanylate cyclase, which in turn increases the production of cyclic guanosine monophosphate and leads to a reduction of the intracellular calcium concentration Apart from regulating vascular tone through vasodilation, nitric oxide also mediates other important vascular homeostatic functions by exerting inhibitory effects on the proliferation of vascular smooth muscle,42 counteracting leukocyte adhesion to the endothelium,43,44 and inhibiting platelet aggregation.45 The endothelium also mediates hyperpolarization of the vascular smooth muscle to cause relaxation.46,47 Although the identity of the endothelium-derived hyperpolarizing factor remains elusive, its hyperpolarizing mechanism is considered to be mediated by calcium-activated potassium channels on vascular smooth muscle.48–51 Candidates include epoxyeicosatrienoic acids,52,53 potassium ion,54 gap junctions,55 hydrogen peroxide,56 and C-type natriuretic peptide.57 It has been suggested that endothelium-derived hyperpolarizing factor might play a compensatory role for the loss of nitric oxide–mediated vasodilation in patients with heart failure.58,59 Other endothelium-derived vasodilators include prostacyclin and bradykinin Prostacyclin is produced via the cyclooxygenase pathway and acts independently of nitric oxide to cause vasodilation.60 It also acts synergistically with nitric oxide to inhibit platelet aggregation Prostacyclin appears to have a limited role in humans in the control of vascular tone Bradykinin stimulates the release of nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor Regulation of vascular tone by the endothelium is also accomplished by the control of vasoconstrictor tone through the release of endothelin61 and the conversion of angiotensin I to angiotensin II at its surface.62 Endothelin-1, the predominant endothelin isoform in the cardiovascular system, binds to ETA receptors on vascular smooth muscle cells to cause vasoconstriction.63 At lower concentrations, however, endothelin-1 causes transient vasodilation in the human forearm circulation,64 probably owing to the release of nitric oxide and prostacyclin via ETB receptors located on endothelial cells.65