Blood vessels are biological pipelines for transporting blood. They can be divided into arteries, veins and capillary according to the transportation direction. Arteries carry blood from the heart to body tissues, veins bring blood from the tissues back to the heart, and microvessels connect arteries and veins, and are the main place for blood and tissue exchange. Different blood vessels have different types of blood vessels. Open circulation organisms, such as insects, have only arteries. The blood flows out of the veins and comes into direct contact with the tissues of the body. The blood is then recovered from the openings in the heart. Closed circulation organisms, such as mammals, birds, reptiles, and fish, connect capillaries with arteries, then connect to veins, and finally return to the heart.
Figure 1. Blood vessels.
Extracellular matrix proteins form the basic structure of blood vessels. Along with providing basic structural support to blood vessels, matrix proteins interact with different sets of vascular cells via cell surface integrin or non-integrin receptors. Such interactions induce vascular cell de novo synthesis of new matrix proteins during blood vessel development or remodeling. Under pathological conditions, vascular matrix proteins undergo proteolytic processing, yielding bioactive fragments to influence vascular wall matrix remodeling. Vascular cells also produce alternatively spliced variants that induce vascular cell production of different matrix proteins to interrupt matrix homeostasis, leading to increased blood vessel stiffness; vascular cell migration, proliferation, or death; or vascular wall leakage and rupture. Destruction of vascular matrix proteins leads to vascular cell or blood-borne leukocyte accumulation, proliferation, and neointima formation within the vascular wall; blood vessels prone to uncontrolled enlargement during blood flow diastole; tortuous vein development; and neovascularization from existing pathological tissue microvessels.
Figure 2. Elastin expression, cross-linking, and assembly.
Figure 3. Collagen.
Figure 4. Fibronectin.
Mature elastin is an insoluble and hydrophobic protein formed by cross-linking of its precursor, tropoelastin — a 68–74 kDa monomeric protein from elastin mRNA alternative splicing normally produced by SMCs in the media and by fibroblasts in the adventitia, released to the extracellular space for cross-linking and elastin fiber formation with the assistance of lysyl oxidase and the helper proteins fibulin-4 or -5. Elastin deposition is limited to the media layer extending from the internal to external elastin laminae. Elastin is the dominant ECM in the arterial wall, comprising 50% of its dry weight, and is the largest component of elastic fiber, comprising ~ 90% of elastic fiber total weight. Elastin fiber consists of fibrillin microfibrils and is embedded within an amorphous core of elastin that allows the elastic recoil. Arteries are subject to extensive mechanical stress induced by arterial blood pressure. In addition to mechanical integrity, elastic laminae contribute to the elasticity of the arteries. Recoil of the arterial wall therefore is a critical mechanism for the continuation of blood flow during diastole when cardiac ejection is ceased. Fibrillin-rich microfibrils provide a structural scaffold to guide elastin deposition and assembly. Elastic fibers are found throughout the vessel wall in the medial layer, where they arrange in concentric fenestrated elastic laminae. Each elastic lamina alternates and is physiologically connected with a concentric ring of SMCs, forming the lamellar unit — the functional resilient unit of the arterial wall.
Collagen is a very stiff protein that limits vessel distension. Collagen includes at least 24 different subtypes and ~ 38 distinct polypeptide chains, depending on the structures and functions of vessels. Different cell types also express different types of collagen. In the normal and injured arterial walls, type I and type III collagens (collagen-I and collagen-III) are the main types in the media and adventitia. Collagens also interact with vascular cells (e.g., SMCs, ECs, and fibroblasts) and play important roles in vascular cell biology and pathobiology. Collagens participate in SMC differentiation, adhesion, migration, proliferation, and apoptosis. Both β1 integrin and the discoidin-domain receptor (DDR) family members mediate these collagen activities. α1β1 integrin stimulates SMC proliferation by activating ERKs in the MAPK pathway. The α2β1 integrin signaling pathway is important to vascular SMC adhesion, proliferation, and differentiation on polymerized fibrillar collagens. α10β1 and α11β1 integrins mediate collagen-dependent mesenchymal nonmuscle cell adhesion and chemotaxis. In vivo, depletion of β1 integrin at the onset of SMC differentiation caused failure to assemble ECM, resulting in lethality prior to birth. DDR1–collagen interaction also regulated SMC migration and proliferation, and MMP production. Ddr1−/− mice had decreased SMC proliferation after vascular injury.
Fibronectin is a dimeric multidomain glycoprotein in plasma and in tissue ECM. This 440 kDa glycoprotein of the ECM is linked by two disulfide bonds located at the C-terminus. It is produced and secreted by numerous cell types including SMCs, fibroblasts, and myofibroblasts, and is widely distributed in ECM. Fibronectin function in the vasculatures is mediated by α5β1 integrin, which is expressed by ECs, SMCs, and fibroblasts. Fibronectin binding to cell surface α5β1 integrin uses the RGD sequence within the 10th type III globular β-sheet repeat of fibronectin. This binding is required for fibronectin matrix assembly and signaling.
All seven fibulins, except fibulin-3, have been found during cardiovascular development, and mostly are induced after injury. Like most other vascular wall matrix proteins, fibulins exhibit their functions by interacting with integrin, but the activity most characteristic of fibulins is interaction with other ECM proteins, such as elastin, fibronectin, and proteoglycan. Fibulins participate with fibronectin in blood clotting. Interaction between fibulins and tropoelastin assists elastin assembly (Figure. 2). Fibulin-1 and fibulin-2 also bind to the C-type lectin-like domain of aggregating proteoglycans including versican, aggrecan, and probably other lecticans.
Figure 5. Fibulins.
Ju H.; et al. Extracellular matrix and cardiovascular diseases. Canadian Journal of Cardiology. 1996, 12(12):1259-67.